Methylation-dependent loss of RIP3 expression in cancer represses programmed necrosis in response to chemotherapeutics

Gi Bang Koo, Michael J. Morgan, Da Gyum Lee, Woo Jung Kim, Jung Ho Yoon, Ja Seung Koo, Seung Il Kim, Soo Jung Kim, Mi Kwon Son, Soon Sun Hong, Jean M.Mulcahy Levy, Daniel A. Pollyea, Craig T. Jordan, Pearlly Yan, David Frankhouser, Deedra Nicolet, Kati Maharry, Guido Marcucci, Kyeong Sook Choi, Hyeseong ChoAndrew Thorburn, You Sun Kim

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129 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)707-725
Number of pages19
JournalCell Research
Volume25
Issue number6
DOIs
Publication statusPublished - 2015 Jun 4

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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    Koo, G. B., Morgan, M. J., Lee, D. G., Kim, W. J., Yoon, J. H., Koo, J. S., Kim, S. I., Kim, S. J., Son, M. K., Hong, S. S., Levy, J. M. M., Pollyea, D. A., Jordan, C. T., Yan, P., Frankhouser, D., Nicolet, D., Maharry, K., Marcucci, G., Choi, K. S., ... Kim, Y. S. (2015). Methylation-dependent loss of RIP3 expression in cancer represses programmed necrosis in response to chemotherapeutics. Cell Research, 25(6), 707-725. https://doi.org/10.1038/cr.2015.56