| Autor: |
Kurt IC; Brain Cancer Research and Therapy Laboratory, Koç University School of Medicine, Istanbul 34450, Turkey., Sur I; Brain Cancer Research and Therapy Laboratory, Koç University School of Medicine, Istanbul 34450, Turkey., Kaya E; Brain Cancer Research and Therapy Laboratory, Koç University School of Medicine, Istanbul 34450, Turkey., Cingoz A; Brain Cancer Research and Therapy Laboratory, Koç University School of Medicine, Istanbul 34450, Turkey., Kazancioglu S; Brain Cancer Research and Therapy Laboratory, Koç University School of Medicine, Istanbul 34450, Turkey., Kahya Z; Brain Cancer Research and Therapy Laboratory, Koç University School of Medicine, Istanbul 34450, Turkey., Toparlak OD; Koç University School of Medicine, Istanbul 34450, Turkey., Senbabaoglu F; Brain Cancer Research and Therapy Laboratory, Koç University School of Medicine, Istanbul 34450, Turkey., Kaya Z; Koç University School of Medicine, Istanbul 34450, Turkey., Ozyerli E; Brain Cancer Research and Therapy Laboratory, Koç University School of Medicine, Istanbul 34450, Turkey., Karahüseyinoglu S; Koç University School of Medicine, Istanbul 34450, Turkey., Lack NA; Koç University School of Medicine, Istanbul 34450, Turkey.; Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada., Gümüs ZH; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Onder TT; Koç University School of Medicine, Istanbul 34450, Turkey., Bagci-Onder T; Brain Cancer Research and Therapy Laboratory, Koç University School of Medicine, Istanbul 34450, Turkey. |
| Abstrakt: |
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can selectively kill tumor cells. TRAIL resistance in cancers is associated with aberrant expression of the key components of the apoptotic program. However, how these components are regulated at the epigenetic level is not understood. In this study, we investigated novel epigenetic mechanisms regulating TRAIL response in glioblastoma multiforme (GBM) cells by a short-hairpin RNA loss-of-function screen. We interrogated 48 genes in DNA and histone modification pathways and identified KDM2B, an H3K36-specific demethylase, as a novel regulator of TRAIL response. Accordingly, silencing of KDM2B significantly enhanced TRAIL sensitivity, the activation of caspase-8, -3 and -7 and PARP cleavage. KDM2B knockdown also accelerated the apoptosis, as revealed by live-cell imaging experiments. To decipher the downstream molecular pathways regulated by KDM2B, levels of apoptosis-related genes were examined by RNA-sequencing upon KDM2B loss, which revealed derepression of proapoptotic genes Harakiri (HRK), caspase-7 and death receptor 4 (DR4) and repression of antiapoptotic genes. The apoptosis phenotype was partly dependent on HRK upregulation, as HRK knockdown significantly abrogated the sensitization. KDM2B-silenced tumors exhibited slower growth in vivo. Taken together, our findings suggest a novel mechanism, where the key apoptosis components are under epigenetic control of KDM2B in GBM cells. |
