Cancer Cell
Previews The Wind God Promotes Lung Cancer Steven M. Frisch1,* and Michael D. Schaller1 1Department of Biochemistry and Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, WV 26506, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.ccr.2014.04.022
In this issue of Cancer Cell, Li and colleagues demonstrate that the hematopoietic transcription factor Aiolos (named after the Wind God of Greek mythology) confers anoikis resistance in lung tumor cells through repression of cell adhesion-related genes including the mechanosensor p66Shc. Co-opting programming factors ordinarily found only in alternative cell lineages for the purpose of evading anoikis has been reported in other settings, for example, activation of the neuronal trkB and NGF genes in breast cancer. The paper by Li et al. (2014) in this issue of Cancer Cell provides provocative evidence that lung cancer cells utilize a hematopoietic transcription factor, Aiolos, to drive both anoikis resistance and anchorage independence. Aiolos/Ikaros family zinc finger 3 (IKZF3) is a member of the Ikaros family of lymphocyte maturation-driving transcription factors (originally described by the Georgopoulis laboratory), which also includes Eos, Helios, and Pegasus. Aiolos is expressed late in B- and T cell maturation, when cells become independent of attachment to the bone microenvironment and prepare to circulate (John and Ward, 2011). Initial studies to define the role of these transcription factors in cancer progression naturally focused upon hematopoietic malignancies. Most studies have examined Ikaros, the founding member of the family with tumor suppressor function that, when mutated, generates aberrant anoikis-resistant precursors to B cell acute lymphoblastic leukemia (Joshi et al., 2014). However, there are scenarios where Ikaros family members have a protumorigenic function in hematopoietic cancers. For example, Aiolos expression is elevated in chronic lymphocytic leukemia and is proposed to promote cell survival by regulation of Bcl2 family proteins (Billot et al., 2011). Aberrant expression of Ikaros family members in solid tumors, including lung and ovarian cancers has been reported, but a unifying concept of their function in solid tumors has not emerged. Li et al. (2014) significantly advance these
studies by providing unique insight into the mechanisms through which Aiolos subverts normal epithelial cell function to drive phenotypes associated with malignant disease. Aiolos and its relatives repress transcription through chromatin remodeling factors including the NuRD and CtBP complexes (Mandel and Grosschedl, 2010). Interestingly, both of these complexes have been implicated widely in tumorigenesis, the latter being a critical factor for epithelial-mesenchymal transition (EMT) and accompanying acquisition of resistance to anoikis (Grooteclaes et al., 2003), and, in this connection, Ikaros is implicated in ovarian cancer cells in the control of expression of several genes associated with EMT. Li et al. (2014) demonstrate that Aiolos represses a number of integrin and tight junction genes, thus inhibiting both cell-matrix and cell-cell adhesion. The ensuing breakdown of cell polarity may well drive anoikis resistance through Wnt, TGF-b, and Hippo pathways acting in concert, as reviewed recently (Frisch et al., 2013). In addition, Aiolos also specifically repressed expression of the p66 isoform of Shc, which may have a profound effect upon anoikis via multiple mechanisms. The p66Shc repression is of unique importance, because this protein, an alternative splice variant of the SHC1 gene (that also encodes p52Shc, a mitogenic tyrosine kinase receptor adaptor protein), is critical for anoikis sensitivity in diverse normal and tumor cell types (Ma et al., 2007). The Terada lab reported previously, using ectopic expression and knockdown approaches, that p66Shc is a mechanosensory component that translates changes in cell-matrix tension occurring in matrix detachment or reattachment into cell death or survival responses (Ma et al., 2007). RhoA
was proposed to become hyperactive in p66Shc-expressing detached cells, generating outward force that is unopposed by matrix and engaging an anoikis triggering mechanism (Ma et al., 2007). Li et al. (2014) now demonstrate that p66Shc is a direct target of repression by Aiolos, which interacts with enhancer elements and interferes with enhancerpromoter interactions (shown by chromatin conformation capture), establishing repressive histone modifications (Figure 1). Identification of the enhancer protein(s) driving p66Shc expression may shed additional light upon both this repression mechanism and the regulation of this gene more broadly. Importantly, the re-expression of p66Shc in Aiolosexpressing cells restored anoikis sensitivity and anchorage dependence, demonstrating the functional significance of Aiolos-dependent p66Shc repression. Alternative mechanisms involving the loss of cell adhesion molecules and resulting depolarization were not explored, and the possibility that these adhesion molecules act in part through regulating p66Shc has not been excluded. This mechanism is certainly plausible given that p66Shc upregulation by cell confluence has been noted (Ma et al., 2007). Examination of human lung tumor samples demonstrated the significance of Aiolos and p66Shc in tumor biology robustly. Expression of Aiolos occurred commonly in small cell lung cancer and, to a lesser extent, non-small cell lung cancer. Aiolos expression correlated with poor prognosis and inversely correlated with p66Shc expression. Several mechanisms for apoptosis induction and tumor suppression by p66Shc have been proposed. One is a profound inhibition of Ras activation, thus activating Rho and contributing to the ‘‘(un)opposed tension’’ model
Cancer Cell 25, May 12, 2014 ª2014 Elsevier Inc. 551
Cancer Cell
Previews
Figure 1. Proposed Mechanism for Anoikis Resistance in Lung Cancer Cells via the Overexpression of Aiolos In normal epithelial cells, detachment engages a p66Shc-mediated response to the loss of cell tension that triggers anoikis (upper panel). With Aiolos expression in lung cancer cells, this pathway is obviated due to the repression of p66Shc as well as other cell adhesion related genes.
mentioned above (Ma et al., 2010). Another is the generation of mitochondrial reactive oxygen species (ROS) through electron transport between p66Shc and cytochrome c, triggering the apoptotic mitochondrial permeability transition, perhaps by peroxidation of cardiolipin (Giorgio et al., 2005). Additionally, p66Shc represses the expression of the transcription factor Nrf, thereby indirectly downregulating antioxidant genes, increasing ROS levels. Consistent with its pro-oxidant activity, p66Shc is an anti-longevity gene in mouse models and was also shown to exacerbate insulin resistance and glucose intolerance (Soliman et al., 2014). Deficiency of p66Shc contributes to the increased carbon flux through the glycolytic pathway as well as the pentose phos-
phate and hexosamine biosynthetic pathways (Soliman et al., 2014). These effects were mediated by p66Shc’s apparent interference with the stimulation of mTOR by growth factors. In light of the importance of these metabolic pathways in anoikis, this may provide an additional mechanism by which Aiolos regulates anoikis through p66Shc. REFERENCES
Grooteclaes, M., Deveraux, Q., Hildebrand, J., Zhang, Q., Goodman, R.H., and Frisch, S.M. (2003). Proc. Natl. Acad. Sci. USA 100, 4568–4573. John, L.B., and Ward, A.C. (2011). Mol. Immunol. 48, 1272–1278. Joshi, I., Yoshida, T., Jena, N., Qi, X., Zhang, J., Van Etten, R.A., and Georgopoulos, K. (2014). Nat. Immunol. 15, 294–304. Li, X., Xu, Z., Du, W., Zhang, Z., Wei, Y., Wang, H., Zhu, Z., Qin, L., Wang, L., Niu, Q., et al. (2014). Cancer Cell 25, this issue, 575–589. Ma, Z., Myers, D.P., Wu, R.F., Nwariaku, F.E., and Terada, L.S. (2007). J. Cell Biol. 179, 23–31.
Billot, K., Soeur, J., Chereau, F., Arrouss, I., Merle-Be´ral, H., Huang, M.E., Mazier, D., Baud, V., and Rebollo, A. (2011). Blood 117, 1917–1927.
Ma, Z., Liu, Z., Wu, R.F., and Terada, L.S. (2010). Oncogene 29, 5559–5567.
Frisch, S.M., Schaller, M., and Cieply, B. (2013). J. Cell Sci. 126, 21–29.
Mandel, E.M., and Grosschedl, R. (2010). Curr. Opin. Immunol. 22, 161–167.
Giorgio, M., Migliaccio, E., Orsini, F., Paolucci, D., Moroni, M., Contursi, C., Pelliccia, G., Luzi, L., Minucci, S., Marcaccio, M., et al. (2005). Cell 122, 221–233.
Soliman, M.A., Abdel Rahman, A.M., Lamming, D.W., Birsoy, K., Pawling, J., Frigolet, M.E., Lu, H., Fantus, I.G., Pasculescu, A., Zheng, Y., et al. (2014). Sci. Signal. 7, ra17.
552 Cancer Cell 25, May 12, 2014 ª2014 Elsevier Inc.
Previews The Wind God Promotes Lung Cancer Steven M. Frisch1,* and Michael D. Schaller1 1Department of Biochemistry and Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, WV 26506, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.ccr.2014.04.022
In this issue of Cancer Cell, Li and colleagues demonstrate that the hematopoietic transcription factor Aiolos (named after the Wind God of Greek mythology) confers anoikis resistance in lung tumor cells through repression of cell adhesion-related genes including the mechanosensor p66Shc. Co-opting programming factors ordinarily found only in alternative cell lineages for the purpose of evading anoikis has been reported in other settings, for example, activation of the neuronal trkB and NGF genes in breast cancer. The paper by Li et al. (2014) in this issue of Cancer Cell provides provocative evidence that lung cancer cells utilize a hematopoietic transcription factor, Aiolos, to drive both anoikis resistance and anchorage independence. Aiolos/Ikaros family zinc finger 3 (IKZF3) is a member of the Ikaros family of lymphocyte maturation-driving transcription factors (originally described by the Georgopoulis laboratory), which also includes Eos, Helios, and Pegasus. Aiolos is expressed late in B- and T cell maturation, when cells become independent of attachment to the bone microenvironment and prepare to circulate (John and Ward, 2011). Initial studies to define the role of these transcription factors in cancer progression naturally focused upon hematopoietic malignancies. Most studies have examined Ikaros, the founding member of the family with tumor suppressor function that, when mutated, generates aberrant anoikis-resistant precursors to B cell acute lymphoblastic leukemia (Joshi et al., 2014). However, there are scenarios where Ikaros family members have a protumorigenic function in hematopoietic cancers. For example, Aiolos expression is elevated in chronic lymphocytic leukemia and is proposed to promote cell survival by regulation of Bcl2 family proteins (Billot et al., 2011). Aberrant expression of Ikaros family members in solid tumors, including lung and ovarian cancers has been reported, but a unifying concept of their function in solid tumors has not emerged. Li et al. (2014) significantly advance these
studies by providing unique insight into the mechanisms through which Aiolos subverts normal epithelial cell function to drive phenotypes associated with malignant disease. Aiolos and its relatives repress transcription through chromatin remodeling factors including the NuRD and CtBP complexes (Mandel and Grosschedl, 2010). Interestingly, both of these complexes have been implicated widely in tumorigenesis, the latter being a critical factor for epithelial-mesenchymal transition (EMT) and accompanying acquisition of resistance to anoikis (Grooteclaes et al., 2003), and, in this connection, Ikaros is implicated in ovarian cancer cells in the control of expression of several genes associated with EMT. Li et al. (2014) demonstrate that Aiolos represses a number of integrin and tight junction genes, thus inhibiting both cell-matrix and cell-cell adhesion. The ensuing breakdown of cell polarity may well drive anoikis resistance through Wnt, TGF-b, and Hippo pathways acting in concert, as reviewed recently (Frisch et al., 2013). In addition, Aiolos also specifically repressed expression of the p66 isoform of Shc, which may have a profound effect upon anoikis via multiple mechanisms. The p66Shc repression is of unique importance, because this protein, an alternative splice variant of the SHC1 gene (that also encodes p52Shc, a mitogenic tyrosine kinase receptor adaptor protein), is critical for anoikis sensitivity in diverse normal and tumor cell types (Ma et al., 2007). The Terada lab reported previously, using ectopic expression and knockdown approaches, that p66Shc is a mechanosensory component that translates changes in cell-matrix tension occurring in matrix detachment or reattachment into cell death or survival responses (Ma et al., 2007). RhoA
was proposed to become hyperactive in p66Shc-expressing detached cells, generating outward force that is unopposed by matrix and engaging an anoikis triggering mechanism (Ma et al., 2007). Li et al. (2014) now demonstrate that p66Shc is a direct target of repression by Aiolos, which interacts with enhancer elements and interferes with enhancerpromoter interactions (shown by chromatin conformation capture), establishing repressive histone modifications (Figure 1). Identification of the enhancer protein(s) driving p66Shc expression may shed additional light upon both this repression mechanism and the regulation of this gene more broadly. Importantly, the re-expression of p66Shc in Aiolosexpressing cells restored anoikis sensitivity and anchorage dependence, demonstrating the functional significance of Aiolos-dependent p66Shc repression. Alternative mechanisms involving the loss of cell adhesion molecules and resulting depolarization were not explored, and the possibility that these adhesion molecules act in part through regulating p66Shc has not been excluded. This mechanism is certainly plausible given that p66Shc upregulation by cell confluence has been noted (Ma et al., 2007). Examination of human lung tumor samples demonstrated the significance of Aiolos and p66Shc in tumor biology robustly. Expression of Aiolos occurred commonly in small cell lung cancer and, to a lesser extent, non-small cell lung cancer. Aiolos expression correlated with poor prognosis and inversely correlated with p66Shc expression. Several mechanisms for apoptosis induction and tumor suppression by p66Shc have been proposed. One is a profound inhibition of Ras activation, thus activating Rho and contributing to the ‘‘(un)opposed tension’’ model
Cancer Cell 25, May 12, 2014 ª2014 Elsevier Inc. 551
Cancer Cell
Previews
Figure 1. Proposed Mechanism for Anoikis Resistance in Lung Cancer Cells via the Overexpression of Aiolos In normal epithelial cells, detachment engages a p66Shc-mediated response to the loss of cell tension that triggers anoikis (upper panel). With Aiolos expression in lung cancer cells, this pathway is obviated due to the repression of p66Shc as well as other cell adhesion related genes.
mentioned above (Ma et al., 2010). Another is the generation of mitochondrial reactive oxygen species (ROS) through electron transport between p66Shc and cytochrome c, triggering the apoptotic mitochondrial permeability transition, perhaps by peroxidation of cardiolipin (Giorgio et al., 2005). Additionally, p66Shc represses the expression of the transcription factor Nrf, thereby indirectly downregulating antioxidant genes, increasing ROS levels. Consistent with its pro-oxidant activity, p66Shc is an anti-longevity gene in mouse models and was also shown to exacerbate insulin resistance and glucose intolerance (Soliman et al., 2014). Deficiency of p66Shc contributes to the increased carbon flux through the glycolytic pathway as well as the pentose phos-
phate and hexosamine biosynthetic pathways (Soliman et al., 2014). These effects were mediated by p66Shc’s apparent interference with the stimulation of mTOR by growth factors. In light of the importance of these metabolic pathways in anoikis, this may provide an additional mechanism by which Aiolos regulates anoikis through p66Shc. REFERENCES
Grooteclaes, M., Deveraux, Q., Hildebrand, J., Zhang, Q., Goodman, R.H., and Frisch, S.M. (2003). Proc. Natl. Acad. Sci. USA 100, 4568–4573. John, L.B., and Ward, A.C. (2011). Mol. Immunol. 48, 1272–1278. Joshi, I., Yoshida, T., Jena, N., Qi, X., Zhang, J., Van Etten, R.A., and Georgopoulos, K. (2014). Nat. Immunol. 15, 294–304. Li, X., Xu, Z., Du, W., Zhang, Z., Wei, Y., Wang, H., Zhu, Z., Qin, L., Wang, L., Niu, Q., et al. (2014). Cancer Cell 25, this issue, 575–589. Ma, Z., Myers, D.P., Wu, R.F., Nwariaku, F.E., and Terada, L.S. (2007). J. Cell Biol. 179, 23–31.
Billot, K., Soeur, J., Chereau, F., Arrouss, I., Merle-Be´ral, H., Huang, M.E., Mazier, D., Baud, V., and Rebollo, A. (2011). Blood 117, 1917–1927.
Ma, Z., Liu, Z., Wu, R.F., and Terada, L.S. (2010). Oncogene 29, 5559–5567.
Frisch, S.M., Schaller, M., and Cieply, B. (2013). J. Cell Sci. 126, 21–29.
Mandel, E.M., and Grosschedl, R. (2010). Curr. Opin. Immunol. 22, 161–167.
Giorgio, M., Migliaccio, E., Orsini, F., Paolucci, D., Moroni, M., Contursi, C., Pelliccia, G., Luzi, L., Minucci, S., Marcaccio, M., et al. (2005). Cell 122, 221–233.
Soliman, M.A., Abdel Rahman, A.M., Lamming, D.W., Birsoy, K., Pawling, J., Frigolet, M.E., Lu, H., Fantus, I.G., Pasculescu, A., Zheng, Y., et al. (2014). Sci. Signal. 7, ra17.
552 Cancer Cell 25, May 12, 2014 ª2014 Elsevier Inc.
