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Review

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MicroRNAs and epigenetic mechanisms of rhabdomyosarcoma development夽

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Maciej Cie´sla, Józef Dulak ∗ , Alicja Józkowicz ∗ Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Gronostajowa 7, 30-387 Krakow, Poland

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Article history: Received 10 February 2014 Received in revised form 4 May 2014 Accepted 5 May 2014 Available online xxx

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Keywords: microRNAs Epigenetic modifications Oxidative stress Heme oxygenase-1 Rhabdomyosarcoma

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Contents

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1. 2. 3. 4. 5. 6.

Rhabdomyosarcoma is the most common type of soft tissue sarcoma in children. Two main subtypes of rhabdomyosarcoma with different molecular pattern and distinct clinical behaviour may be identified – embryonal and alveolar rhabdomyosarcoma. All types of rhabdomyosarcoma are believed to be of myogenic origin as they express high levels of myogenesis-related factors. They all, however, fail to undergo a terminal differentiation which results in tumour formation. In the aberrant regulation of myogenesis in rhabdomyosarcoma, microRNAs and epigenetic factors are particularly involved. Indeed, these mediators seem to be even more significant for the development of rhabdomyosarcoma than canonical myogenic transcription factors like MyoD, a master regulatory switch for myogenesis. Therefore, in this review we focus on the regulation of rhabdomyosarcoma progression by microRNAs, and especially on microRNAs of the myo-miRNAs family (miR-1, -133a/b and -206), other well-known myogenic regulators like miR-29, and on microRNAs recently recognized to play a role in the differentiation of rhabdomyosarcoma, such as miR-450b-5p or miR-203. We also review changes in epigenetic modifiers associated with rhabdomyosarcoma, namely histone deacetylases and methyltransferases, especially from the Polycomp Group, like Yin Yang1 and Enhancer of Zeste Homolog2. Finally, we summarize how the functioning of these molecules can be affected by oxidative stress and how antioxidative enzymes can influence the development of this tumour. This article is part of a Directed Issue entitled: Rare Cancers. © 2014 Elsevier Ltd. All rights reserved.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Muscle progenitor cells and their possible contribution to RMS development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epigenetic disturbances in RMS development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . MicroRNAs in RMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Oxidative stress in RMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction Rhabdomyosarcoma (RMS) is a rare malignancy of childhood and infancy. Despite its low frequency of onset, it is the most common

夽 This article is part of a Directed Issue entitled: Rare Cancers. ∗ Corresponding author. E-mail addresses: [email protected] (J. Dulak), [email protected] (A. Józkowicz).

soft tissue sarcoma, with an incidence of approximately one per million (Koscielniak et al., 1992). It belongs to a group of small blue round cell tumours. Usually three sub-types of RMS are distinguished, namely embryonal, alveolar and pleomorphic RMS, with distinct phenotypes and clinical features. Embryonal (eRMS) and alveolar (aRMS) RMS are most prevalent, with an incidence of 70% and 20% of RMS cases, respectively (Hayes-Jordan and Andrassy, 2009). They are characterized by entirely different molecular fingerprints. Embryonal RMS, which is associated with a more favourable

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outcome, is heterogeneous in terms of oncogenic mutations, and may include loss of imprinting (LOI) on chromosome 11, mutations in insulin-like growth factor-2 (IGF-2), p16 and p53 genes 47 or epigenetic disturbances e.g. in long intergenic noncoding RNAs 48 (lncRNAs), like H19 (Anderson et al., 1999). Alveolar RMS usually 49 (in 80% of cases) share t(2;13) or t(1;13) translocations, which lead 50 to the formation of fusion protein composed of transcription fac51 tors Pax3 or Pax7, respectively, and FoxO1 domains (Barr et al., 52 1993). Patients with aRMS are more often diagnosed with metas53 tases and generally have shorter overall survival (Missiaglia et al., 54 2012). What is more, the presence of Pax3/7-FoxO1 fusion protein 55 is an independent negative prognostic factor in aRMS. 56 Regardless of sub-type, RMS, like many other neoplasms diag57 nosed at childhood (e.g. acute promyelocytic leukaemia, APL), is 58 believed to be derived from tissue displaying an aberrant differ59 entiation pattern (Charytonowicz et al., 2009). In the case of RMS, 60 the tissue of origin closely resembles the striated skeletal muscle. 61 Indeed, RMS displays a number of features that may link it to the 62 normal muscles, counting among others the high expression of pro63 myogenic proteins such as MyoD, myogenin, desmin or muscle 64 specific microRNAs (miRs-1, -133b or -206). Despite the expres65 sion of these mediators, including a master regulatory switch for 66 myogenesis, MyoD, RMS is retained at different stages of myogenic 67 differentiation. This abnormal pattern of cell maturation is accom68 panied by a number of epigenetic changes, ranging from modified 69 methylation and misbalanced expression of methyltransferases, 70 71Q2 to the disturbed expression of lncRNAs or microRNAs (Onyango and Feinberg, 2009; Taulli et al., 2009). Deciphering these molec72 ular cues is necessary for the validation of putative therapeutic 73 approaches. 74 Until recently a serious issue in RMS studies was the lack of 75 comprehensive insight into the genetic landscape of this tumour 76 and therefore the lack of holistic understanding of the molecular 77 mechanisms that cause the onset of RMS. This started to change 78 due to the rapidly expanding field of deep sequencing technologies 79 and the establishment of novel molecular biology tools. Techniques 80 such as whole genome sequencing, RNA sequencing, exon mapping 81 or the analysis of single nucleotide polymorphisms resulted in the 82 description of novel druggable molecular pathways such as those 83 related to oxidative stress (Chen et al., 2013) or in showing a higher 84 incidence of epigenetic alterations, changes in apoptosis-related 85 genes or protein phosphorylation (Shern et al., 2014). These sen86 sitive techniques enable the tracking not only of gross differences 87 between various sub-types of RMS but also the monitoring of highly 88 dynamic mutation profiles in different sub-sets of cells in an indi89 vidual patient or even in a single tumour (Chen et al., 2013). Such an 90 approach may bring to light new therapeutic targets such as BCOR 91 protein reported by Shern and colleagues (Shern et al., 2013), which 92 were previously out of the scope of interest for researchers in the 93 field. 94 There is scant evidence on mutations governing RMS devel95 opment. This is closely related to another conundrum in RMS 96 studies, which is determining the tumour initiating and propa97 gating cells. Despite papers indicating that progenitor cells for 98 muscle development, termed satellite cells (SCs), may also give 99 rise to RMS (Calhabeu et al., 2013), no direct experiments have so 100 far convincingly shown that this is indeed so. Instead, more and 101 more data demonstrating the presence of different subsets of pro102 genitors within muscular tissue may indicate that, in addition to 103 SCs, there are other possible sources of cells for initiating RMS. 104 This opinion might be supported by the growing number of stud105 ies focusing on gene expression profiles in different cell lineages 106 to which RMS may be related (Blum et al., 2013). Furthermore, 107 RMS can be found not only in the striated muscles but also in 108 the parameninges, testes, head and neck region, retroperitoneum, 109 bladder, and other non-muscular tissues, including bone marrow. 110 45 46

This may suggest that RMS might develop from more primitive cells of mesenchymal lineage, like mesenchymal stromal cells (MSCs) (Charytonowicz et al., 2009) or fibroadipogenic progenitors (FAPs), the adipogenesis-committed cells with some potential to differentiate towards skeletal muscles (Hatley et al., 2012). Pinpointing the cell of origin for RMS might give better insight into RMS biology and might provide an important advantage in tailoring the prospective therapeutic approaches.

2. Muscle progenitor cells and their possible contribution to RMS development RMS is believed to develop from cells that failed to differentiate terminally into striated muscle. In the classical model of myogenesis, the quiescent non-proliferating satellite cells, containing a subset of stem cells with the potential for self-renewal, can be activated either by physiological processes like physical training, or by pathophysiological stimuli like muscle damage, or by disease like muscular dystrophies. In all these circumstances the satellite cells become activated, develop into proliferating and differentiating myoblasts and, in the end, form elongated, polynucleated, myosin rich myotubes (Campion, 1984). Upon stimulation, quiescent Pax7+ MyoD− SCs start to produce MyoD (Buckingham and Relaix, 2007). As RMS usually expresses both these transcription factors, some authors have proposed that the induction of oncogenesis in SC-derived cell lineage by genetic modifications typical for RMS, namely overexpressing Pax3-FoxO1 fusion protein or targeting K-RAS and TP53-dependent pathways, may lead to the development of RMS (Keller et al., 2004). This, however, seems not to be the case. There have been a number of studies aimed at deciphering the cell of origin for RMS. The experiments demonstrated a surprisingly wide range of tumours resulting from the induction of oncogenesis in myogenic precursors. For instance, the forced expression of K-RAS together with TP53 mutation lead to the formation of a variety of sarcomas, including eRMS, when performed specifically in quiescent Pax7+ MyoD− satellite cells. Apparently the same mutations, but induced in the activated Pax7+ MyoD+ satellite cells, lead to the formation of undifferentiated pleomorphic sarcoma, indicating that even cells with close resemblance may give rise to different malignancies, and suggesting the involvement of cis regulatory circuits in RMS development (Blum et al., 2013). So far, attempts to induce the malignant transformation of progenitor cells into eRMS than aRMS have been more effective (Hettmer and Wagers, 2010; Ignatius et al., 2012; Keller et al., 2004; Keller and Capecchi, 2005). Genetic modifications of various progenitors or more differentiated myogenic lineage-committed cells with the Pax3-FoxO1 fusion gene, a stand-alone hallmark of aRMS, were not successful and did not result in the formation of this RMS subtype. Indeed, for the development of aRMS secondary mutations, such as the presence of mutated TP53 or CDKN2A proteins, are required (Keller et al., 2004; Keller and Capecchi, 2005). All of these, together with the description of a different genetic landscape in these two forms of RMS (Chen et al., 2013) may indicate that specific, chromatin structure-related features are indispensable for the development of different forms of RMS. The knock-in (KI) model of aRMS, based on the cell-specific overexpression of a solely Pax3-FoxO1 fusion protein in the maturing, Myf6 expressing myofibers, resulted in the formation of aRMSlike tumours, with a very low incidence of approximately 1%. However, the introduction of a second hit mutation, like TP53 or CDKN2A knock-out (KO), led to the development of aRMS with a much higher penetrance, reaching 100% at 3 months of age in bi-allelic Pax3-FoxO1, homozygous for TP53 KO animals (Nishijo et al., 2009). These spontaneously developing tumours shared the

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protein expression pattern similar to the primary human tumours and exhibited a number of both molecular and clinical features highly similar to aRMS (Kikuchi et al., 2013). The dependency of this model on the second hit mutation, together with the observation that myogenic cells during normal embryonal development may express Pax3-FoxO1 transcript (Yuan et al., 2013) might hint that, under conditions accompanying embryogenesis, this fusion oncogene is capable of playing a physiological role and only in a certain microenvironment, and in a well-defined subset of cells it exhibits oncogenic potential. Delineating this pro-oncogenic environment may be essential to decipher the cell of origin for aRMS. Interestingly, novel subsets of cells residing within the muscle tissue and sorted out as a side population have been identified, which can exhibit the progenitor potential. They include pericytes, PW1+ Pax7− interstitial cells (PICs) or fibroadipogenic progenitors (FAPs) (Fig. 1, Judson et al., 2013). The latter ones, in particular, seem to be important. FAPs contribute to the fatty degeneration of the muscle upon damage or onset of dystrophy (Penton et al., 2013), and provide stimuli for the regeneration of muscle by producing messenger factors for activation and differentiation of satellite cells. They also can fuse with SCs into mature myotubes or undergo adipogenic or fibrogenic maturation (Joe et al., 2010). Given their ability to switch between normal myogenesis and fatty degeneration, FAPs may be attractive candidates for studying the origin of RMS. Recently, eRMS has been shown to develop from aP2 expressing cells with adipogenic commitment, if they were genetically modified to exhibit a disturbed Sonic hedgehog (Shh)-Smoothened (Smo)-Patched (Ptch) signalling pathway (Hatley et al., 2012). Interestingly, the Shh-Smo-Ptch axis itself did not alter either the myogenic or adipogenic differentiation. The introduction of these molecules into the cells of adipogenic lineage resulted in the activation of embryonal skeletal muscle genes, like MyoD, Myf5 or the embryonal class of myosins, that are characteristic for eRMS, as well as the class of genes associated with cell cycle regulation, like Cdkn2a, but only in brown, not white adipose tissue. Moreover, Shh signalling did not evoke tumourigenesis in muscle progenitors of a different origin, including MyoD, Myf5 or PAX3 positive cells (Hatley et al., 2012). Most importantly, the forced overexpression of Smo in Pax7 expressing cells, i.e. satellite cells, did not cause oncogenesis, which does not support the hypothesis about SCs as a source for RMS development. Only the expression of Smo in myogenin-positive cells resulted in tumour formation, though within a strictly defined site of oncogenesis, namely the tongue (Hatley et al., 2012). All these results may indicate that two factors are crucial for eRMS and possibly also aRMS development: (i) a mutation activating the expression of early markers of myogenesis, governing the proliferation of muscle progenitor cells, and (ii) a permissive cellular environment that occurs only within a certain population of cells. A possible transdifferentiation of non-myogenic cells into muscle-related RMS might explain why the myogenic pathway is altered in this tumour. The transdifferentiated cells, whose fate has been initially established, lack the priming signals that enable the completion of myogenesis. This may also suggest that epigenetic changes characteristic rather for non-myogenic than muscle progenitors, might abolish terminal differentiation. Such studies may give a better insight into other muscleassociated diseases, like muscular dystrophies, where the adipogenic deterioration of tissues is a common feature. Interestingly, these two pathological states, i.e. muscular dystrophy and RMS are interconnected, as the dystrophin-deficient dystrophic mdx mice show a higher incidence of spontaneous RMS (Chamberlain et al., 2007). This also indicates the possible role of inflammation, oxidative stress and pathological remodelling of muscles for RMS development.

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3. Epigenetic disturbances in RMS development The process of physiological myogenesis is influenced by a number of molecules. The most important among them are proteins belonging to myogenesis-related factors (MRFs) family, namely Myf5, Myf6 (MRF4), MEF2C, MyoD and myogenin, which sustain a class of basic helix-loop-helix transcription factors governing the central axis of myogenic differentiation (Meadows et al., 2008). All of them are activated during the onset or progression of myogenesis and are subsequently silenced to achieve a final muscular differentiation. The characteristic feature of RMS is a propensity to start differentiation towards skeletal muscles, which is accompanied by an incapability to terminate this process. Numerous studies have focused on elucidating the mechanisms governing the impaired myogenic program in RMS. They have indicated a role for various kinases e.g. p38 MAPK (Rossi et al., 2011), epigenetic factors, e.g. Polycomb Repressor Complex 2 or JARID2 (Walters, 2013), and microRNAs (Yan et al., 2009). As the cell of origin for RMS development may be one of nonmuscular lineage, it has been proposed that RMS tumour formation can be related to the improper epigenetic imprinting of chromatin, hindering the myogenic differentiation (Hatley et al., 2012). Indeed, there is vast evidence for involvement of number of epigenetic modifiers, such as methyl transferases or histone deacetylases to play a putative role in genesis of RMS (Table 1, Lee et al., 2011). For instance, histone deacetylase inhibitors, like valproic acid potentiates pro-apoptotic effect of Pax3-Foxo1 inhibitors (Hecker et al., 2010). This effect is achieved by de-repression of p21, protein modulated by Pax3-Foxo1 fusion protein via EGR1. Interestingly p21 together with p38 MAP kinase pathway, was also shown to promote myogenic differentiation of RMS cells (Raimondi et al., 2012). Histone deacetylase action results in alteration of rather labile methylation and acetylation of chromatin, regulating availability of target genes for transcription factors (e.g. MyoD), enhancers or repressors. Among the epigenetic modifiers that have been shown to be misbalanced in RMS, the Polycomb group (PcG) and particularly two of its members, Enhancer of Zeste Homolog 2 (Ezh2) and Yin Yang-1 (YY1), stands apart. PcG proteins act as repressors of transcription by modification of histones via their methylation at various sites. The PcG family consists of two protein subsets, PcG Repressor Complex-1 (PRC1) and PcG Repressor Complex-2/3/4 (PRC2-4). PRC1 comprises YY1, BMI1, HPH1-3, HPC and RING1AB, while PRC2 contains Ezh2, EED, SUZ11 and RbAp46/48 proteins (Mahmoudi and Verrijzer, 2001). PRC2 and its catalytic subunit Ezh2, mediates the methylation of lysine 27 in histone H3, thereby repressing gene expression (van Heeringen et al., 2013). Notably, it was shown to affect both the proper embryonal myogenesis and the development of RMS (Asp et al., 2011). An important member of the PRC2 group is Ezh2, which promotes oncogenesis in various types of tumours, e.g. in prostate cancer or in acute myeloid leukaemia, and interacts with wellknown oncogenes, such as Myc (Myc regulates Ezh2 via miR-26 downregulation and by direct promoter binding) or PTEN (Ezh2, together with other PcG members is recruited by Evi1 to be promoter of PTEN) (Zardo et al., 2012a,b). In RMS its action is mediated by interfering with molecular pathways that are common for different malignancies (like miR-26a pathway) or that are exclusively myogenic (like the inhibition of MyoD activity) (Caretti et al., 2004). Some studies indicate other possible signalling cues which may be proposed in RMS, e.g. a deregulation of Ezh2-miR-203Notch-MyoD axis. Notch dependent pathways are implicated in the development of various malignancies, including RMS (Belyea et al., 2011; Roma et al., 2012, Raimondi et al., 2013). It is feasible to think about this factor in terms of potential therapies as, unlike

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PICs

FAPs

pericytes

SCs

Myogenic precursor cells muscle development

RMS development Restoration of proliferation,

Abrogation of proliferation,

Blockade of differentiation:

• MyoD axis deregulated

pericytes

PICs

• MyoD axis activated

• miRNAs 1/206 silenced • YY1 activated

• miRNAs 1/206 activated

SCs

• p38 kinase silenced

Promotion of differentiation:

FAPs

• PcG complex activated

• YY1 silenced • p38 kinase activated • PcG complex silenced

Fig. 1. Progenitor cells residing in muscle and their activation resulting in proper myogenesis or aberrant pathways leading to RMS development. In normal conditions, upon activation, various subsets of progenitor cells restore complex muscular tissue. In aberrant, neoplastic conditions they undergo malignant transformation, fail to differentiate, proliferate uncontrollably and form RMS. Abbreviations: SCs – Satellite Cells, FAPs – Fibro Adipogenic Progenitors, PICs – PW1+ /Pax7− Interstitial Cells.

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other putative molecular targets for RMS treatment, its function can be silenced not only using genetic engineering, e.g. RNAi, but also using small molecules designed to inactivate the ␥-secretase, which is indispensable for Notch activation (Sang et al., 2008). The silencing of the Notch pathway leads to the abrogation of molecular mechanisms underlying the impaired differentiation and pronounced invasiveness of RMS. It has been reported that Notch interacts with Hes/Hey1 proteins to influence neuronal

cadherin and ␣9-integrin, and, by doing so, affects the migratory properties of RMS cells (Masià et al., 2012). Interestingly, the expression of Hes/Hey1 is dependent on the Pax3-FoxO1 oncogene (Ahn, 2013). On the other hand, Notch can affect myogenic differentiation by reducing p38 MAP kinase phosphorylation (Raimondi et al., 2012). Through interaction with Hey1 it can also interfere with MyoD transcriptional activity, leading to a decrease in expression of myogenin and Mef2C genes (Buas et al., 2010). As such, Hey1,

Table 1 Epigenetic factors contributing to RMS development. Abbreviations: SMARCD1 – SWI/SNF-related, matrix associated, actin dependent regulator of chromatin. Ezh2 – Enhancer of zeste homolog2. Epigenetic factor

Mode of action in RMS

Citation

DLK-GTL2

Differentially imprinted in eRMS (LOI) and aRMS (EOI)

Schneider et al., 2014

Ezh2/PcG

Promotes differentiation in eRMS Promotes cell death in aRMS H3K27me3 Targets Atrogin1/MAFbx Suppresses miRNA 125b, let-7c, 139-5p, 101 and 200b in HCC Blocks NF␬B signalling via miRNA 31 epigenetic silencing Together with Myc and HDAC3 inhibits miRNA 29

Marchesi et al., 2014; Ciarapica et al., 2014 Ciarapica et al., 2013 Ciarapica et al., 2013 Ciarapica et al., 2013 Au et al., 2012 Yamagishi et al., 2012 Zhang et al., 2012a,b

HDAC1 HDAC4

Recruited by Yin Yang1 to repress miRNA 29 b, c Repressess myogenin and MEF2C function

Wang et al., 2008 Rao et al., 2010, Wang et al., 1999

JARID2

Recruits histone-methylating agents to target genes Direct target of Pax3-FoxO1 Blocks differentiation and is permissive for proliferation of RMS

Walters et al., 2013 Walters et al., 2013 Walters et al., 2013

KMT1A

Abrogates MyoD transcriptional activity Blocks differentiation and is permissive for proliferation of RMS

Lee et al., 2011 Lee et al., 2011

SMARCD1

Chromatin remodeling/bHLH factors abrogation BAF53a subunit

Rao et al., 2010 Taulli et al., 2013

YY1

Recruits Dicer to affect imprinting Synergizes with Smad7 to affect TGF␤ signalling Stabilization of HIF1 and promoting of tumourigenesis Double direction interaction with miRNA 29

Zardo et al., 2012a,b Yan et al., 2014 Wu et al., 2013 Wang et al., 2008

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the protein known to control the switch from cell quiescence to activation, appears to be the major mediator of Notch effects in RMS. Another component of PcG proteins strongly implicated in the development of RMS is YY1. Depending on the presence of other factors, it can function either as a repressor, an activator or an initiator of gene transcription (Thiaville and Kim, 2011). YY1 has been shown to interact with various epigenetic factors like HDAC1/2, p300 or protein arginine N-methyltransferase-1 (PRMT1) (RezaiZadeh et al., 2003). This transcription factor is also the sole member of the PcG complex with the DNA binding domain, recognizing a specific DNA sequence. After recognition of the CCATnTT element, YY1 enables the binding of other PRCs resulting in the formation of heterochromatin within the neighbouring genes. In particular, YY1 has conserved binding sites within the imprinting control regions that can affect the transcription of genes located nearby by cis regulatory mechanisms. Interestingly, it can recruit not only PRCs members but also microRNA processing enzymes, Dicer and Argonaute, tying together microRNAs and epigenetic regulators machineries (Zardo et al., 2012a,b). This remains in agreement with a finding highlighting the possible role of Dicer in the direct sculpting of the chromatin landscape (Giles et al., 2010). YY1 is highly expressed in a number of different tumours and leukaemias, including such malignancies as colorectal cancer, breast cancer, osteosarcoma, Burkitt lymphoma, multiple myeloma or RMS (Nicholson et al., 2011). Due to its ambiguous role in the regulation of gene expression, YY1 can also exhibit various effects on cancer progression, from promoting oncogenesis through very distinct mechanisms (Zhang et al., 2012a,b) up to sensitizing the tumours to treatment with chemotherapeutic agents, such as taxanes (Matsumura et al., 2009). During myogenic development, YY1 decreases the differentiation rate of myoblasts (Caretti et al., 2004). It appears, however, that the action of YY1 in RMS depends on the unique molecular pathway, involving the miR-29 family and NF␬B signalling (Wang et al., 2008). On the other hand, its effect on cancer progression greatly relies on genes that are epigenetically regulated. That action of YY1 is achieved by the recruitment of the PcG member, Ezh2, together with HDAC1, which are chromatin modifying proteins (Tong et al., 2012). Apart from proteins belonging to the PcG family, other epigenetic modifiers were also shown to play a role in the progression of RMS. Among them are: (i) KMT1A methyltransferase, which restrains the entry of aRMS cells into myogenic differentiation (Lee et al., 2011) by interacting with MyoD, (ii) SUV39H1 methyltransferase which interferes with the cell cycle to abrogate formation of eRMS (Albacker et al., 2013) or (iii) H19, a long noncoding RNA, being a hallmark particle improperly imprinted in eRMS, which interacts with the HOTS oncogene (Onyango and Feinberg, 2011). The growing body of data describing the involvement of epigenetic modifications in the development of RMS supports the important role of epigenetic modifiers in oncogenesis and suggests them as potential therapeutic targets. The mechanisms of action of epigenetic modifications are still not completely understood. So far, they have escaped the attention of many studies, very often due to the lack of precise research tools and methods. In recent years, however, there has been rapid progress. Epigenetic modifiers seem to be of special importance in the malignancies of early childhood, including RMS, where a surprisingly low number of canonical regulators, like transcription factors, were convincingly attributed to oncogenesis.

4. MicroRNAs in RMS MicroRNAs, which comprise a class of short non-coding RNAs, have been recognized as master regulators of a plethora of cellular

5

processes. Among others they are strongly implicated in tumour development (Esquela-Kerscher and Slack, 2006). This statement is also true for RMS (Taulli et al., 2009). Molecules of microRNA are believed to tightly control and tune cellular responses in differentiating tissues and may serve as a second line of regulation (and additional degree of complexity) that protects cells from pathological states (Ciesla et al., 2011). As such, they are silenced in various types of tumours that in this way escape the supervision of cellular anti-cancer mechanisms. The best known microRNAs that play a role in the development of RMS belong to miR-1, miR-133a/b and miR-206 myo-miRNA group, i.e. muscle specific microRNAs (Taulli et al., 2009; Yan et al., 2009), and miR-29 family (Wang et al., 2008; Rota et al., 2011), which are more ubiquitously expressed. These microRNAs not only fine-tune RMS progression but may also serve as putative molecular markers of the onset of RMS (Miyachi et al., 2010). MicroRNAs may directly regulate MRFs, mitogen activated kinases, cell cycle genes or growth factors-dependent signal transduction. Interestingly, microRNAs, together with epigenetic factors, seem to be fundamental players in RMS pathology, as they may affect the central hub of muscle differentiation–the MyoD transcription factor (Dey et al., 2011). MyoD, together with myogenin, its downstream protein, may be useful in diagnosing RMS, as they are exclusively expressed in this tumour and not in other types of sarcomas (Armeanu-Ebinger et al., 2012). However, no clear pattern of correlation between MyoD/myogenin expression and RMS clinical outcome has been observed (Keller and Guttridge, 2013). It has been recently reported by Calhabeu and colleagues (Calhabeu et al., 2013) that Pax3-FoxO1 can abrogate MyoD-myogenin signalling. However, though recent publications put much effort in delineating the disturbed MyoD transcriptional activity, results are still vague in terms of detailed mechanism of action. The most comprehensively studied with regards to RMS are myo-miRNAs. They are also well characterized players in physiological muscle differentiation, where they promote entry into further steps of myogenesis by silencing the expression of Pax7, the early activator of myogenic commitment, or by affecting histone deacetylase-4 (HDAC4) and DNA polymerase-␣ (Winbanks et al., 2013). They may promote a more proliferative status during the activation of myoblasts (miR-133a and miR-133b), or favour a final differentiation of muscles (miR-1 and miR-206, Chen et al., 2006). Myo-miRNAs may be either skeletal muscle specific (miR-133b, miR-206) or also expressed in cardiac muscle (miR-1, miR-133a) (Rao et al., 2006). In normal muscle they influence a plethora of cellular cues, leading to cell cycle arrest and terminal differentiation. Myo-miRNAs are strongly downregulated in RMS in comparison to skeletal muscles, therefore they have been proposed as key players and potential inhibitors in RMS oncogenesis (Fig. 2) (Yan et al., 2009; Taulli et al., 2009; Rao et al., 2010; Missiaglia et al., 2010). Indeed, forced overexpression of myo-miRNAs strongly abolishes RMS growth, both in vitro and in xenotransplant experiments, by targeting the pro-proliferative axis dependent on cMET/HGF (hepatocyte growth factor) signalling (Taulli et al., 2009; Yan et al., 2009). Myo-miRNAs cluster on different chromosomes (miR-1-1 with miR-133a-2 on chromosome 20, miR-1-2 with miR-133a-1 on chromosome 18, and miR-206 with miR-133b on chromosome 6) and, though they all share the same seed sequence, they display different expression pattern and slightly different actions in RMS (Kim et al., 2006). Among myo-miRNAs, miR-1 and miR-206 seem to be particularly significant in RMS. Only overexpression of miR-1 and miR-206 may overcome a block in myogenesis observed in RMS (Yan et al., 2009). The forced upregulation of miR-1 arrests eRMS but not aRMS cells in G1/S phase and, at the same time, upregulates the muscle specific genes, like myogenin (Rao et al., 2010). Such effects have

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Fig. 2. Molecular cues representing epigenetic modifiers and microRNAs shown to be deregulated in RMS. miR-206 is a pivotal player tying together various modulatory pathways reported to play a role in RMS biology.

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not been observed for miR-133a. Taulli and colleagues reported that miR-206 blocks cMET expression, thereby abrogating tumour cells survival (Taulli et al., 2009). Low levels of miR-206 are also an independent negative prognostic factor for RMS clinical outcome, but only in eRMS or in aRMS lacking Pax3/7-FoxO1 fusion protein (Missiaglia et al., 2010). The lack of correlation between miR-206 expression and progress of disease in patients with Pax3/7-FoxO1 positive aRMS (Missiaglia et al., 2010), together with the lack of cell cycle arrest in aRMS but not eRMS cells engineered to overexpress miR-1 (Rao et al., 2010), may have farther, possibly also clinical, implications. To understand these associations we must first, however, clarify the molecular mechanisms of Pax3/7-FoxO1 activity. In both myoblasts and RMS, miR-206 controls the availability of E-protein in the MyoD complex, regulating in this way the proliferation to differentiation switch in RMS (Macquarrie et al., 2012). Generally, miR-206 seems to affect most pathways that have been shown to play a role in RMS development, ranging from MAPK activity or inflammatory response, through the regulation of epigenetic factors, to the direct and indirect regulation of MyoD activity (Fig. 2). Thus, it appears to orchestrate the molecular changes leading to the development of RMS. In particular, miR206 affects interleukin-4 dependent signalling (Missiaglia et al., 2010) and, thereby, innate immunity. This mechanism has already been reported to affect fibroadipogenic progenitor functions and to promote pro-myogenic action of FAPs (Heredia et al., 2013). It was also shown that the abrogation of the interleukin-4 receptor (IL4R) blocks the fusion of RMS with satellite cells and abolishes tumour progression (Li et al., 2012).miR-206 has been reported to affect NF␬B signalling (Missiaglia et al., 2010). This pathway can also be regulated by other microRNAs strongly implicated in RMS development, those belonging to the miR-29 family. In a classical pathway of activation, the NF␬B transcription factor is derepressed in response to the phosphorylation of its repressor, I␬B (Baeuerle and Baltimore, 1988). The activated NF␬≡ was shown to suppress physiological myogenesis (Bakkar et al., 2008) via multiple paths. In particular, it can directly regulate the activity of the YY1 transcription factor. During normal myogenesis, the crucial step for the induction of terminal differentiation is the switch between the active and inactive NF␬B-YY1 complex (Wang et al., 2008). Such a switch results in derepression of miR-29 signalling, which is further accelerated due to miR-29’s capabilities of YY1 silencing. Both in murine myoblasts and in human RMS cell lines, the YY1 effects result from bidirectional interaction between YY1 protein and miRs-29b/c (Guttridge et al., 2000 and Wang et al., 2008). The exact mechanism is not known as, according to the miRanda

bioinformatic algorithm, this regulation occurs despite the lack of predicted binding sites for the miR-29 seed sequence in human YY1 3‘UTR. It has also been proposed that miR-29, similarly to miR206, can silence HDAC4 (Winbanks et al., 2011) or affect the Rybp epigenetic modifier (Zhou et al., 2012) additionally promoting myogenic differentiation. All these interactions are deregulated in RMS, affecting the myogenic programme and facilitating the development of tumours (Wang et al., 2008). The significance of miR-29 in tumour progression is supported by results of experiments where its overexpression blocked the RMS growth in the xenotransplant model, where RMS cells were injected subcutaneously to immunodeficient mice (Wang et al., 2008). Interestingly, miRs-29 and myo-miRNAs dependent pathways may be interconnected, as YY1 affects the expression of miR-1, miR-133a/b and miR-206, as well (Lu et al., 2012). Also, according to recent findings, miR-206 and miR-29 signalling may be tied together in RMS by action of transforming growth factor-␤1 (TGF␤1, Winbanks et al., 2011 and discussed in Novák et al., 2013), which regulates additionally miR-450b-5p expression to block terminal myogenic differentiation in RMS (Sun et al., 2013). Complex interactions between TGF signalling and miR-29, miR-206 and miR450b-5p are mediated by members of Smad proteins family. For example, miR-450b-5p tie together several molecular pathways. This miR is affected by Smad3 and 4, but not Smad2 protein to influence ecto-NOX disulfide-thiol exchanger 2 (ENOX2) and paired box 9 (Pax9). Restoration of miR-450b-5p in RMS results in arrested cell growth and enhanced MyoD signalling both in vitro and in in vivo xenotransplant experiment (Sun et al., 2013). Also molecular cue linking together miR-206 and miR-29 pathways in RMS may also depend on effects elicited by those microRNAs on the expression of Pax3 and proteins regulating cell cycle, like CCND2 (Li et al., 2012). Again, discrepancies between eRMS and aRMS occur, as aRMS cells escape microRNA-mediated silencing of Pax3 by expression of Pax3-FoxO1 fusion protein. Apart from these most thoroughly studied molecules, a number of other microRNAs have been reported to play an important role in the induction and progression of RMS. One example could be the well-known oncomir complex, miR-17-92 cluster, encoded within the C13orf25 gene, which is amplified in some RMS (Williamson et al., 2007). It is also worth mentioning a novel factor, miR-203, that is silenced by the promoter hypermethylation in RMS (Diao et al., 2014). They all lead to dysregulated proliferation or aberrant myogenic differentiation. In summary, RMS is characterized by the misbalanced expression of a number of microRNAs that are involved in the regulation of myogenic differentiation. The expression of the majority of miRNAs is decreased in RMS, which is consistent with the well-denoted observation that tumours escape suppressive mechanisms, including those that are miRNA-dependent. A brief overview of miRNAs deregulated in RMS is presented in Table 2.

5. Oxidative stress in RMS The development of tumours, including RMS, and especially the functioning of pivotal cancer initiating cells, can be potently influenced by hypoxia and oxidative stress (Chen et al., 2013; Blein et al., 2014; Liu et al., 2014; Das et al., 2008, reviewed in: Shyh-Chang et al., 2013). The role of the metabolic switch in cancer cells from aerobic towards glycolytic in normoxic conditions – a phenomenon known for a long time as the Warburg effect, has been described in detail (Lu et al., 2002). Also, the significance of low oxygen tension both in the growth of tumours and in maintaining the stem cell niche is commonly accepted (e.g. Mathieu et al., 2013). Importantly, hypoxia was shown to enhance specific features of satellite cells, like the engraftment potency after transplantation

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Table 2 MicroRNAs contributing to RMS development. Abbreviations: HDAC4 – histone deacetylase 4, DNA pol ␣ – DNA polymerase ␣, Rybp – Ring1 and YY1 binding protein. microRNA

Target genes

Mode of action in RMS

Citation

miR-9 miR-17-92 miR-26a

E-cadherin Thrombospondin-1 Ezh2

Elevated in aRMS Localized within C13orf25 gene amplified in RMS Decreased in RMS

Armeanu-Ebinger et al., 2012 Williamson et al., 2007 Ciarapica et al., 2009

miR-29

YY1 Rybp

Restoration of myogenesis and cell cycle arrest Restoration of myogenesis

Wang et al., 2008 Zhou et al., 2012

miR-185

Six1 (cyclin a1 and cMyc)

Direct link in RMS was not shown

Imam et al., 2010

miR-200c

E-cadherin

Decreased in aRMS Increases metastatic potential Indirect up regulation of E-cadherin

Armeanu-Ebinger et al., 2012

miR-203

JAK/STAT, Notch

Silenced by promoter hypermethylation in RMS

Diao et al., 2014

miR-206

cMET NF␬B IL 4 HDAC4 DNA pol ␣ ERK/JNK musculin

Block of metastases and proliferation

Taulli et al., 2009 Missiaglia et al., 2010 Missiaglia et al., 2010

ENOX, Pax9

Inhibited by TGFb1 in Smad3 and 4 dependent manner

miR-450b-5p

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Pax7, MEF2C repression Cell cycle arrest and differentiation Indirect interaction

(Liu et al., 2012), and to modulate the stem cell niche or tumour microenvironment. Thus, hypoxia leads to a drop in the expression of miRNA-1 and miRNA-206 via the conserved Notch/Hes/Hey pathway, which eventually results in the upregulation of Pax7. This can play a role in both normal myogenesis and the formation of RMS (Majmundar et al., 2012). Indeed, it has been shown that satellite cells as well as cancer initiating cells need low oxygen tensions for retaining their unique features (Mimeault and Batra, 2013). In a physiological state, hypoxic conditions are limited to the stem cell niche beneath the basal lamina. Herein, hypoxia facilitates asymmetric divisions and the self-renewal of stem cells (Liu et al., 2012). In the tumour environment, however, there are multiple areas which are characterized by different oxygen tensions (Casazza et al., 2013). Noteworthy, even within the established stable cell lines derived from pediatric tumours, including neuroblastoma and RMS, there are fractions of cells with a higher metastatic and migratory potential (Das et al., 2008). They are defined as a side population in cell sorting, and their number increases in hypoxic cultures. Such cells have the augmented capacity to migrate towards hypoxic areas within the tumour, led by the gradient of the stromal cell derived factor-1 (SDF-1) (Das et al., 2008). The effect of hypoxia on RMS is possibly mediated by the hypoxia inducible factor-1 (HIF-1), which is highly expressed in RMS cell lines (Fig. 3A). Interestingly, the overexpression of this transcription factor in cardiomyocytes can result in the formation of RMS-like structures (Lei et al., 2008). The stabilization of HIF-1 protein in RMS depends on changes in the epigenetic fingerprint, namely in the hypermethylation of P4HTM prolyl hydroxylase promoter. This results in the sustained activation of HIF-1-modified pathways, leading to pronounced tumourigenesis (Mahoney et al., 2012). Skeletal muscle cells have a unique aerobic capacity and can rapidly adapt to short-term anaerobic activity (Chen et al., 2013). As a consequence, muscle cells also have a robust antioxidant defence system protecting them from the deleterious effects of excessive generation of reactive oxygen species (ROS). Similarly, rhabdomyosarcoma cells have elevated ROS levels due to their increased metabolic activity, oncogenic stimulation, and mitochondrial dysfunction (Chen et al., 2013). They also display an exceptionally high expression of gluthatione synthetase (Zitka et al., 2012). Hence, oxidative stress seems to be a very important

Sun et al., 2013

factor influencing RMS, and this cancer may be particularly susceptible to therapeutics that increase ROS, or that target the ability of cells to protect against oxidative stress (Minai et al., 2013; Chen et al., 2013). In accordance with this supposition we have recently shown that forced overexpression of heme oxygenase-1 (HO-1), an enzyme involved in response to oxidative stress, strongly abolishes the differentiation of the murine myoblast cell line and murine satellite cells (Kozakowska et al., 2012). HO-1 catalyzes the degradation of heme to biliverdin, carbon monoxide (CO) and ferrous iron (Jozkowicz et al., 2007). Its upregulation leads to the decreased generation of ROS and improved survival of myoblasts in a prooxidative environment (Kozakowska et al., 2012). Nevertheless, the effect of HO-1 overexpression on myogenic differentiation did not rely on antioxidative protection. Instead, it was mediated by a COdependent decrease in the activation of MyoD expression by the CCAAT enhancer binding protein delta (cEBP␦) and concomitant lack of upregulation of myogenin and myo-miRNAs (Kozakowska et al., 2012). It was also associated with higher levels of SDF-1 and miR-146a which, by targeting Numb, a Notch inhibitor, may exert an anti-myogenic effect (Kuang et al., 2009). Importantly, we found that HO-1 is highly upregulated in RMS, especially in aRMS cell lines (Kozakowska et al., 2012, Fig. 3B). Interestingly, in contrast to myoblasts where HO-1 is a cytoplasmic protein, in RMS it is localized mostly in the nucleus (Fig. 3B), where it can possibly function independently of its enzymatic activity (Lin et al., 2007). HO-1 and its transcriptional activator, nuclear factor erythroid2 related factor 2 (Nrf2) were shown to affect tumour growth and to promote tumourigenesis (Loboda et al., 2008). It has also been reported recently that Nrf2 affects the lung carcinoma metabolism by influencing glucose utilization through driving it towards pentose phosphate pathway and tricarboxylic acids cycle. Concomitantly, it abrogates miR-1/206 cues by abolishing HDAC4 action (Singh et al., 2013). Hence, the effect of Nrf2 appears to be similar to HO-1 inhibiting myomirs expression in C2C12 cells (Kozakowska et al., 2012). Interestingly, miR-1/206 abolishes the metabolic switch towards the pentose phosphate cycle (Singh et al., 2013). This goes in line with our unpublished findings showing that HO-1 overexpressing murine myoblasts are characterized by higher levels of genes involved in glycolytic metabolism. Complex interactions between oxidative stress-related genes like Nrf2, HO-1 and different factors influencing tumourigenesis are depicted in Fig. 4.

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Fig. 3. Expression of hypoxia and oxidative stress related factors in RMS (A) hypoxia inducible factor 1 (HIF1) and (B) heme oxygenase-1 (HO-1) in different RMS cell lines. eRMS (RD) and aRMS (RH5, RH18 and RH28) cells are characterized by different sub-cellular localization of HO-1.

Fig. 4. Possible role of HO-1 and Nrf2 pathways in muscle differentiation and RMS development. HO-1 and Nrf2 may affect a wide range of factors contributing to the development of RMS, like metabolic switch, uncontrolled proliferation or cell migration and homeostasis. Abbreviations: cEBP␦ – CCAAT enhancer binding protein ␦, CO – carbon monoxide, cGMP – cyclic GMP, SDF1 – stromal cell derived factor 1.

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for drug screening. One such successful study was used to investigate the compounds affecting protein kinase C iota in aRMS mouse model (Kikuchi et al., 2013). Also, the rapidly expanding field of deep sequencing studies and whole genome sequencing has already resulted in the more sensitive and specific identification of molecular cues that affect RMS pathophysiology and are potentially prone to targeted therapies. There is growing evidence on the importance of factors that, until recently, were elusive and very difficult for measuring using canonical tools of molecular biology. Good examples are the epigenetic changes sculpting the RMS genome, deregulation of the myogenesis related microRNAs or subtle changes in the metabolome, such as the disturbed balance between the generation of reactive oxygen species and efficacy of cellular antioxidative mechanisms. Due to better insight into these issues, the forthcoming years may hopefully bring promising therapeutic approaches in the treatment of rare sarcomas, like RMS. It is becoming increasingly clear that in order to fulfil this goal we need a deeper understanding of how molecular pathways, like epigenetic modifications, oxidative stress or microRNAs, may affect the onset of RMS.

6. Concluding remarks

Acknowledgments

It can be expected that the better understanding of molecular mechanisms governing the development of RMS may result in establishing more successful therapies with fewer side effects. Indeed, the generation of animal models characterized by the high penetration of tumourigenic phenotype, which closely resemble the onset of RMS, has already proved to be a suitable platform

The research on muscle differentiation and tumourigenesis in the authors’ laboratory is supported by grants from the Foundation for Polish Science (VENTURES, No. 2011- Q3 7/2 and 2013-11/2) and the National Science Centre (MAESTRO, No. NCN 2012/06/A/NZ1/00004; HARMONIA, No NCN 2012/06/M/NZ1/00008 and OPUS, No NCN 2012/07/B/NZ1/02881).

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MicroRNAs and epigenetic mechanisms of rhabdomyosarcoma development.

Rhabdomyosarcoma is the most common type of soft tissue sarcoma in children. Two main subtypes of rhabdomyosarcoma with different molecular pattern an...
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