Epigenetic regulation of the miR142-3p/interleukin-6 circuit in glioblastoma

Guang-Yuh Chiou, Chian Shiu Chien, Mong Lien Wang, Ming Teh Chen, Yi Ping Yang, Yung Luen Yu, Yueh Chien, Yun Ching Chang, Chiung Chyi Shen, Chung Ching Chio, Kai Hsi Lu, Hsin I. Ma, Kuan Hsuan Chen, Dean-Mo Liu, Stephanie A. Miller, Yi Wei Chen, Pin I. Huang, Yang Hsin Shih, Mien Chie Hung*, Shih Hwa Chiou

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

53 Scopus citations

Abstract

Epigenetic regulation plays a critical role in glioblastoma (GBM) tumorigenesis. However, how microRNAs (miRNAs) and cytokines cooperate to regulate GBM tumor progression is still unclear. Here, we show that interleukin-6 (IL-6) inhibits miR142-3p expression and promotes GBM propagation by inducing DNA methyltransferase 1-mediated hypermethylation of the miR142-3p promoter. Interestingly, miR142-3p also suppresses IL-6 secretion by targeting the 3' UTR of IL-6. In addition, miR142-3p also targets the 3' UTR and suppresses the expression of high-mobility group AT-hook 2 (HMGA2), leading to inhibition of Sox2-related stemness. We further show that HMGA2 enhances Sox2 expression by directly binding to the Sox2 promoter. Clinically, GBM patients whose tumors present upregulated IL-6, HMGA2, and Sox2 protein expressions and hypermethylated miR142-3p promoter also demonstrate poor survival outcome. Orthotopic delivery of miR142-3p blocks IL-6/HMGA2/Sox2 expression and suppresses stem-like properties in GBM-xenotransplanted mice. Collectively, we discovered an IL-6/miR142-3p feedback-loop-dependent regulation of GBM malignancy that could be a potential therapeutic target.

Original languageEnglish
Pages (from-to)693-706
Number of pages14
JournalMolecular Cell
Volume52
Issue number5
DOIs
StatePublished - 12 Dec 2013

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