Tumor Biol. DOI 10.1007/s13277-014-1961-6
Stat3 inhibits Beclin 1 expression through recruitment of HDAC3 in nonsmall cell lung cancer cells Li-Jun Miao & Feng-Xiang Huang & Zhen-Tao Sun & Rui-Xia Zhang & Shi-Fu Huang & Jing Wang
Received: 12 February 2014 / Accepted: 10 April 2014 # International Society of Oncology and BioMarkers (ISOBM) 2014
Abstract Recent studies have shown that Beclin 1, a key regulator of autophagic process, is frequently downregulated and may serve as an independent prognostic biomarker for nonsmall cell lung cancer. However, the molecular mechanisms underlying its downregulation remain poorly understood. The signal transducer and activator of transcription 3 (Stat3) is a transcription factor which plays a crucial role for multiple tumor growth and progression. Here, we demonstrate that Beclin 1 is a direct transcriptional target of Stat3 in lung cancer cells. Interleukin-6 (IL-6) treatment or transfection of a constitutively activated Stat3 in AGS and NCI-H1650 cells inhibited Beclin 1 expression. At the molecular level, we further revealed that Stat3 could directly bind to the promoter region of Beclin 1 and repressed its transcription through recruiting histone deacetylase 3 (HDAC3). Collectively, our results suggest that the activated Stat3 may represent an important mechanism for Beclin 1 downregulation in nonsmall cell lung cancer development.
Keywords Nonsmall cell lung cancer . Stat3 . Beclin 1 . HDAC3
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Introduction Nonsmall cell lung cancer (NSCLC) represents 80–85 % of lung cancers, which has become one of the leading causes of cancer-related deaths and a substantial cancer burden worldwide . However, its causal factors and molecular pathogenesis remain largely unknown . Autophagy, a process of programmed cell survival, is critical for balancing sources of energy in response to nutrient deprivation [3, 4]. Beclin 1, the mammalian orthologue of yeast Atg6, has a central role in the initiation of autophagy by forming the Beclin 1 interacting complex . Beclin 1 deficiency in mice is tightly associated with susceptibility to metabolic stress, DNA damage, and subsequently a high incidence of spontaneous tumors, including lymphoma and hepatocellular and lung carcinoma [6, 7]. In addition, reduced messenger RNA (mRNA) and protein expression of Beclin 1 is found in the primary tumor in NSCLC, suggesting that Beclin 1 may serve as a candidate tumor suppressor gene . However, the molecular mechanisms underlying its downregulation remain poorly understood. Signal transducer and activator of transcription 3, also known as Stat3, is a transcription factor activated by cytokines and growth factors, such as interleukin 6 (IL-6) [9, 10]. Recent evidences have shown that aberrant Stat3 is constitutively activated and essential for cell growth, proliferation, and metastasis in multiple human cancers . In the present study, we speculate that Stat3 activation may regulate Beclin 1 expression in NSCLC cells.