Epigenetic downregulation of STAT6 increases HIF-1α expression via mTOR/S6K/S6, leading to enhanced hypoxic viability of glioma cells.

Multifunctional signal transducer and activator of transcription proteins play important roles in cancer. Here, we have shown that 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 duanyu18136 promoter by DNA methyltransferases. duanyu18136 interacts with Rheb under hypoxia and inhibits mTOR/S6K/S6 signaling, in turn, inducing increased HIF-1α translation. duanyu18136 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 duanyu18136 with the aid of DNA methyltransferase inhibitors, such as 5-aza-2-deoxycytidine, for treatment of gliomas.

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