Identification of MYC as an antinecroptotic protein that stifles RIPK1–RIPK3 complex formation

Daehyeon Seong, Manhyung Jeong, Jinho Seo, Ji Yoon Lee, Chi Hyun Hwang, Ho Chul Shin, Jeong Yoon Shin, Young Woo Nam, Jeong Yeon Jo, Haeseung Lee, Hye Jung Kim, Hwa Ryeon Kim, Ji Hoon Oh, Sang Jun Ha, Seung Jun Kim, Jae Seok Roe, Wankyu Kim, June Won Cheong, Kwang Hee Bae, Sang Chul LeeAndrew Oberst, Peter Vandenabeele, Dong Hoon Shin, Eun Woo Lee, Jaewhan Song

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

The underlying mechanism of necroptosis in relation to cancer is still unclear. Here, MYC, a potent oncogene, is an antinecroptotic factor that directly suppresses the formation of the RIPK1–RIPK3 complex. Gene set enrichment analyses reveal that the MYC pathway is the most prominently down-regulated signaling pathway during necroptosis. Depletion or deletion of MYC promotes the RIPK1–RIPK3 interaction, thereby stabilizing the RIPK1 and RIPK3 proteins and facilitating necroptosis. Interestingly, MYC binds to RIPK3 in the cytoplasm and inhibits the interaction between RIPK1 and RIPK3 in vitro. Furthermore, MYC-nick, a truncated form that is mainly localized in the cytoplasm, prevented TNF-induced necroptosis. Finally, down-regulation of MYC enhances necroptosis in leukemia cells and suppresses tumor growth in a xenograft model upon treatment with birinapant and emricasan. MYC-mediated suppression of necroptosis is a mechanism of necroptosis resistance in cancer, and approaches targeting MYC to induce necroptosis represent an attractive therapeutic strategy for cancer.

Original languageEnglish
Pages (from-to)19982-19993
Number of pages12
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number33
DOIs
StatePublished - Aug 2020

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