Journal
ACTA NEUROPATHOLOGICA COMMUNICATIONS
Volume 7, Issue 1, Pages -Publisher
BMC
DOI: 10.1186/s40478-019-0798-z
Keywords
STAT6; DNA hypermethylation; Glioma; HIF-1 alpha; mTOR; Rheb
Categories
Funding
- National Research Foundation of Korea (NRF) - Korea government (MSIT) [NRF-2012R1A5A2048183]
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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-1 alpha 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.
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