Abstract
Multifunctional signal transducer and activator of transcription (STAT) proteins play important roles in cancer. Here, we have shown that STAT6 is epigenetically silenced in some cases of malignant glioblastoma, which facilitates cancer cell survival in a hypoxic microenvironment. This downregulation results from hypermethylation of CpG islands within the STAT6 promoter by DNA methyltransferases. STAT6 interacts with Rheb under hypoxia and inhibits mTOR/S6K/S6 signaling, in turn, inducing increased HIF-1α translation. STAT6 silencing and consequent tumor-promoting effects are additionally observed in glioma stem-like cells (GSC). Despite recent advances in cancer treatment, survival rates have shown little improvement. This is particularly true in the case of glioma, where multimodal treatment and precision medicine is needed. Our study supports the application of epigenetic restoration of STAT6 with the aid of DNA methyltransferase inhibitors, such as 5-aza-2-deoxycytidine, for treatment of STAT6-silenced gliomas.
Highlights
Epigenetic modifications comprising DNA methylations and histone modifications both qualitatively and quantitatively alter gene expression [15, 36]
We propose that STAT6 downregulation resulting from DNA methyltransferase (DNMT)-mediated hypermethylation of promoter CpG islands facilitates accumulation of HIF-1α through Mammalian target of rapamycin (mTOR) activation in hypoxia and consequent enhancement of glioma cell survival. mTOR activation via STAT6 knockdown is achieved through suppression of direct interactions between STAT6 and Rheb that inhibit HIF-1α translation
Western blot analyses demonstrated that, whereas STAT2 and STAT4 showed no prominent or consistent changes in expression, STAT1, STAT3 and STAT5 expression were increased in glioma tissues compared with neighboring non-tumor tissue
Summary
Epigenetic modifications comprising DNA methylations and histone modifications both qualitatively and quantitatively alter gene expression [15, 36]. Recent genome-wide DNA methylation analyses and large-scale epigenetic profiling studies have revealed widespread distribution of epigenetic markers as well as frequent epigenetic alterations in a variety of human malignancies, establishing a causative role for an altered epigenome in carcinogenesis [1]. The predominant modification of mammalian DNA is cytosine methylation, followed by adenine and guanine methylation [17]. Methylation of cytosine bases in mammalian DNA has been primarily described in the context of CpG dinucleotides. Methylation of cytosine in the promoter region may repress expression of the corresponding gene by preventing the binding of specific transcription factors or attracting mediators of chromatin remodeling, such as histone-modifying enzymes or other repressors of gene expression
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