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MYC Induces Oncogenic Stress through RNA Decay and Ribonucleotide Catabolism in Breast Cancer

JK. Meena, JH. Wang, NJ. Neill, D. Keough, N. Putluri, P. Katsonis, AM. Koire, H. Lee, EA. Bowling, S. Tyagi, M. Orellana, R. Dominguez-Vidaña, H. Li, K. Eagle, C. Danan, HC. Chung, AD. Yang, W. Wu, SJ. Kurley, BM. Ho, JR. Zoeller, CM. Olson, KL....

. 2024 ; 14 (9) : 1699-1716. [pub] 20240904

Jazyk angličtina Země Spojené státy americké

Typ dokumentu časopisecké články

Perzistentní odkaz   https://www.medvik.cz/link/bmc24018992

Grantová podpora
R35GM147123 National Institute of General Medical Sciences (NIGMS)
T32 GM120011 NIGMS NIH HHS - United States
1F30CA278316-01 National Cancer Institute (NCI)
RR200076 Cancer Prevention and Research Institute of Texas (CPRIT)
R00 ES030735 NIEHS NIH HHS - United States
1R01CA215452-01 National Cancer Institute (NCI)
P30 CA125123 NCI NIH HHS - United States
Q-0007 Welch Foundation (The Welch Foundation)
T32GM120011 National Institutes of Health (NIH)
RR150093 Cancer Prevention and Research Institute of Texas (CPRIT)
R01 CA215226 NCI NIH HHS - United States
C5470/A27144 Mark Foundation For Cancer Research (The Mark Foundation for Cancer Research)
R01 CA215452 NCI NIH HHS - United States
U01CA214125 National Cancer Institute (NCI)
PDF17487931 Susan G. Komen (SGK)
R00ES030735 National Institute of Environmental Health Sciences (NIEHS)
1W81XWH-18-1-0573 U.S. Department of Defense (DOD)
LX22NPO5103 National Institute of Virology and Bacteriology
1R01CA215226 National Cancer Institute (NCI)
P30 DK056338 NIDDK NIH HHS - United States
S10 RR024574 NCRR NIH HHS - United States
U01 CA214125 NCI NIH HHS - United States
F30 CA278316 NCI NIH HHS - United States
R35 GM147123 NIGMS NIH HHS - United States

Upregulation of MYC is a hallmark of cancer, wherein MYC drives oncogenic gene expression and elevates total RNA synthesis across cancer cell transcriptomes. Although this transcriptional anabolism fuels cancer growth and survival, the consequences and metabolic stresses induced by excess cellular RNA are poorly understood. Herein, we discover that RNA degradation and downstream ribonucleotide catabolism is a novel mechanism of MYC-induced cancer cell death. Combining genetics and metabolomics, we find that MYC increases RNA decay through the cytoplasmic exosome, resulting in the accumulation of cytotoxic RNA catabolites and reactive oxygen species. Notably, tumor-derived exosome mutations abrogate MYC-induced cell death, suggesting excess RNA decay may be toxic to human cancers. In agreement, purine salvage acts as a compensatory pathway that mitigates MYC-induced ribonucleotide catabolism, and inhibitors of purine salvage impair MYC+ tumor progression. Together, these data suggest that MYC-induced RNA decay is an oncogenic stress that can be exploited therapeutically. Significance: MYC is the most common oncogenic driver of poor-prognosis cancers but has been recalcitrant to therapeutic inhibition. We discovered a new vulnerability in MYC+ cancer where MYC induces cell death through excess RNA decay. Therapeutics that exacerbate downstream ribonucleotide catabolism provide a therapeutically tractable approach to TNBC (Triple-negative Breast Cancer) and other MYC-driven cancers.

Citace poskytuje Crossref.org

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