Volume 25, No 6, Jun 2015
ISSN: 1001-0602
EISSN: 1748-7838 2018
impact factor 17.848*
(Clarivate Analytics, 2019)
Volume 25 Issue 6, June 2015: 707-725
ORIGINAL ARTICLES
Methylation-dependent loss of RIP3 expression in cancer represses programmed necrosis in response to chemotherapeutics
Gi-Bang Koo1,2,*, Michael J Morgan3,*, Da-Gyum Lee1, Woo-Jung Kim1,2, Jung-Ho Yoon1,2, Ja Seung Koo4, Seung Il Kim5, Soo Jung Kim6, Mi Kwon Son6, Soon Sun Hong6, Jean M Mulcahy Levy7, Daniel A Pollyea8, Craig T Jordan8, Pearlly Yan9, David Frankhouser9, Deedra Nicolet9,10, Kati Maharry9,10, Guido Marcucci9, Kyeong Sook Choi1,2, Hyeseong Cho1,2, Andrew Thorburn3 and You-Sun Kim1,2
1Department of Biochemistry, Ajou University School of Medicine, Suwon 443-380, Korea
2Department of Biomedical Sciences, Graduate School, Ajou University, Suwon 443-380, Korea
3Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA
4Department of Pathology, Yonsei University College of Medicine, Seoul 120-752, Korea
5Department of Surgery, Yonsei University College of Medicine, Seoul 120-752, Korea
6Department of Biomedical Sciences, College of Medicine, Inha University, Incheon 402-751, Korea
7Department of Pediatrics, University of Colorado Denver, Aurora 80045, CO 80045, USA
8Division of Hematology, Hematologic Malignancies and Stem Cell Transplantation, University of Colorado School of Medicine, Aurora, CO, USA
9Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
10Alliance for Clinical Trials in Oncology Statistics and Data Center, Mayo Clinic, Rochester, MN 55905, USA
Correspondence: You-Sun Kim(yousunkim@ajou.ac.kr)
Receptor-interacting protein kinase-3 (RIP3 or RIPK3) is an essential part of the cellular machinery that executes “programmed” or “regulated” necrosis. Here we show that programmed necrosis is activated in response to many chemotherapeutic agents and contributes to chemotherapy-induced cell death. However, we show that RIP3 expression is often silenced in cancer cells due to genomic methylation near its transcriptional start site, thus RIP3-dependent activation of MLKL and downstream programmed necrosis during chemotherapeutic death is largely repressed. Nevertheless, treatment with hypomethylating agents restores RIP3 expression, and thereby promotes sensitivity to chemotherapeutics in a RIP3-dependent manner. RIP3 expression is reduced in tumors compared to normal tissue in 85% of breast cancer patients, suggesting that RIP3 deficiency is positively selected during tumor growth/development. Since hypomethylating agents are reasonably well-tolerated in patients, we propose that RIP3-deficient cancer patients may benefit from receiving hypomethylating agents to induce RIP3 expression prior to treatment with conventional chemotherapeutics.
10.1038/cr.2015.56
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