Identification of MYC As an Antinecroptotic Protein That Stifles RIPK1-RIPK3 Complex Formation

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2020 Aug 6

PMID 32753382

Citations 21

Authors

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 Lee

Andrew Oberst

Peter Vandenabeele

Dong Hoon Shin

Eun-Woo Lee

Jaewhan Song

Affiliations

Soon will be listed here.

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.

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