Methylation-Dependent Loss of RIP3 Expression in Cancer Represses Programmed Necrosis in Response to Chemotherapeutics
Koo, Gi-Bang | Morgan, Michael J. | Lee, Da-Gyum | Kim, Woo-Jung | Yoon, Jung-Ho | Koo, Ja Seung | Kim, Seung Il | Kim, Soo Jung | Son, Mi Kwon | Hong, Soon Sun | Levy, Jean M. Mulcahy | Pollyea, Daniel A. | Jordan, Craig T. | Yan, Pearlly | Frankhouser, David | Nicolet, Deedra | Maharry, Kati | Marcucci, Guido | Choi, Kyeong Sook | Cho, Hyeseong | Thorburn, Andrew | Kim, You-Sun
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 RIP3 expression is often silenced in cancer cells due to genomic methylation near its transcriptional start site, so 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 when compared to normal tissue in 85% of breast cancer patients, suggesting that RIP3 deficiency is selected for 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.
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