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 Cho; Andrew Thorburn; You Sun Kim

doi:10.1038/cr.2015.56

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

Department of Pathology

Research output: Contribution to journal › Article › peer-review

308 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 language	English
Pages (from-to)	707-725
Number of pages	19
Journal	Cell Research
Volume	25
Issue number	6
DOIs	https://doi.org/10.1038/cr.2015.56
Publication status	Published - 2015 Jun 4

Bibliographical note

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© 2015 IBCB, SIBS, CAS All rights reserved.

All Science Journal Classification (ASJC) codes

Molecular Biology
Cell Biology

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/cr.2015.56

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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

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title = "Methylation-dependent loss of RIP3 expression in cancer represses programmed necrosis in response to chemotherapeutics",

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.",

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

year = "2015",

month = jun,

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doi = "10.1038/cr.2015.56",

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Koo, GB, Morgan, MJ, Lee, DG, Kim, WJ, Yoon, JH, Koo, JS, Kim, SI, Kim, SJ, Son, MK, Hong, SS, Levy, JMM, Pollyea, DA, Jordan, CT, Yan, P, Frankhouser, D, Nicolet, D, Maharry, K, Marcucci, G, Choi, KS, Cho, H, Thorburn, A & Kim, YS 2015, 'Methylation-dependent loss of RIP3 expression in cancer represses programmed necrosis in response to chemotherapeutics', Cell Research, vol. 25, no. 6, pp. 707-725. https://doi.org/10.1038/cr.2015.56

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AU - Koo, Gi Bang

AU - Morgan, Michael J.

AU - Lee, Da Gyum

AU - Kim, Woo Jung

AU - Yoon, Jung Ho

AU - Koo, Ja Seung

AU - Kim, Seung Il

AU - Kim, Soo Jung

AU - Son, Mi Kwon

AU - Hong, Soon Sun

AU - Levy, Jean M.Mulcahy

AU - Pollyea, Daniel A.

AU - Jordan, Craig T.

AU - Yan, Pearlly

AU - Frankhouser, David

AU - Nicolet, Deedra

AU - Maharry, Kati

AU - Marcucci, Guido

AU - Choi, Kyeong Sook

AU - Cho, Hyeseong

AU - Thorburn, Andrew

AU - Kim, You Sun

PY - 2015/6/4

Y1 - 2015/6/4

N2 - 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.

AB - 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.

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

Abstract

Bibliographical note

All Science Journal Classification (ASJC) codes

UN SDGs

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