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- W2010550430 abstract "Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CAEmerging evidence indicates that alteration of epigenetic regulation might be a key event for cancer progression. Abnormal expression of histone methyltransferase G9a, which contributes to transcriptional repression of tumor suppressor genes, has been implicated in maintaining cancer cells proliferation. Recent study suggests that inhibition of G9a reduces cancer cell growth. However, its molecular process has not been fully explored. In this study, we show that G9a expression is positively correlated to poor prognosis in head and neck squamous cell carcinoma (HNSCC) patients. Knockdown of G9a or inhibition of its catalytic activity by bix-01294 in HNSCC cells reduced proliferation, colony formation and anchorage-independent growth without inducing necrosis or apoptosis. Instead, complementary approaches including immunoblot analysis, LC3-GFP-fluorescent microscopy and morphologic study by electron microscopy revealed inhibition of G9a inducing autophagy. Pre-treatment with autophagy inhibitor 3-methyladenine (3-MA) or chloroquine (CQ) antagonized the inhibition effect of bix-01294 on cells viability, demonstrating that autophagic cell death is the major consequences in G9a suppressed cells. Mechanistic investigation suggested that ERK phosphatase, DUSP4, may be a downstream target of G9a. Knockdown of G9a and then suppression of DUSP4 expression restored ERK phosphorylation and colony formation but inhibits autophagy induced by G9a silencing. This effect was further reversed by treatment with MAPK/ERK selective inhibitor U0126. Moreover, knockdown of G9a resulted in growth inhibition and autophagy in orthotopic tumor model in mice. Taken together, our results not only point out the mechanism of autophagic cell death induced by inhibition of G9a but also pave a way for new targeting therapy utility for HNSCC in clinical.Citation Format: KAI-CHUN LI, KUO-TAI HUA, CHING-TING TAN, MIN-LIANG KUO. Inhibition of G9a induces DUSP4-dependent autophagic cell death in head and neck squamous cell carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1332. doi:10.1158/1538-7445.AM2014-1332" @default.
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- W2010550430 date "2014-09-30" @default.
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- W2010550430 title "Abstract 1332: Inhibition of G9a induces DUSP4-dependent autophagic cell death in head and neck squamous cell carcinoma" @default.
- W2010550430 doi "https://doi.org/10.1158/1538-7445.am2014-1332" @default.
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