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.

中文翻译：

---

STAT6的表观遗传下调通过mTOR / S6K / S6增加HIF-1α表达，从而导致神经胶质瘤细胞缺氧生存能力增强。

多功能信号转导子和转录激活子（STAT）蛋白在癌症中起重要作用。在这里，我们已经表明，在恶性胶质母细胞瘤的某些情况下，STAT6在表观遗传上是沉默的，这有助于在缺氧的微环境中促进癌细胞的存活。这种下调是由于DNA甲基转移酶使STAT6启动子内的CpG岛超甲基化所致。STAT6在缺氧条件下与Rheb相互作用，并抑制mTOR / S6K / S6信号传导，进而诱导HIF-1α翻译增加。在神经胶质瘤干样细胞（GSC）中还观察到STAT6沉默和随之而来的肿瘤促进作用。尽管最近在癌症治疗方面取得了进展，但存活率却没有多少改善。对于需要多式联运治疗和精准医学的神经胶质瘤尤其如此。