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Survivin downregulation by histone methyl transferase inhibitor BIX-01294 pretreatment overcomes resistance of hepatic cell carcinoma cells to TNF-related apoptosis-inducing ligand
Yena Namgung1, So Young Kim2, Hyori Kim1,3, Seak Hee Oh4, Young Hoon Sung1,3, Inki Kim1,3,*
1Department of Convergence Medicine, University of Ulsan College of Medicine,
2Biomedical Research Center and 3Convergence Medicine Research Center, ASAN Institute for Life Sciences, ASAN Medical Center,
4Department of pediatrics, ASAN Medical center
Abstract
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a cancer-selective cell death-inducing agent with little or no toxicity in normal cells. However, various human cancers and cancer cell lines were reported to be resistant to TRAIL. In this study, we isolated BIX-01294, a euchromatic histone methyl transferase (EHMT2 or G9a) inhibitor, as a sensitizer of TRAIL in the Huh7 cell line. Analysis of various hepatic cell carcinoma (HCC) cell lines by proliferation assays, western blotting, and flow cytometry revealed that BIX-01294 is a potent sensitizing agent of TRAIL in Huh7, HepG2, and SNU475 cells. From a mechanistic perspective, BIX-01294 downregulated the anti-apoptotic protein survivin in all tested HCC cells, and survivin expression knockdown by small-interference RNA sensitized HCC cells to TRAIL, suggesting a regulatory role for G9a in the expression of anti-apoptotic proteins including survivin. Based on our results, EHMT2 inhibition by BIX-01294 may be a potent anti-tumor therapeutic strategy for human hepatic cell carcinomas.
Abstract, Accepted Manuscript(in press) [Submitted on July 6, 2018, Accepted on October 11, 2018]
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