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Table S2 from MYC Induces Oncogenic Stress through RNA Decay and Ribonucleotide Catabolism in Breast Cancer

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posted on 2024-09-04, 07:40 authored by Jitendra K. Meena, Jarey H. Wang, Nicholas J. Neill, Dianne Keough, Nagireddy Putluri, Panagiotis Katsonis, Amanda M. Koire, Hyemin Lee, Elizabeth A. Bowling, Siddhartha Tyagi, Mayra Orellana, Rocio Dominguez-Vidaña, Heyuan Li, Kenneth Eagle, Charles Danan, Hsiang-Ching Chung, Andrew D. Yang, William Wu, Sarah J. Kurley, Brian M. Ho, Joseph R. Zoeller, Calla M. Olson, Kristen L. Meerbrey, Olivier Lichtarge, Arun Sreekumar, Clifford C. Dacso, Luke W. Guddat, Dominik Rejman, Dana Hocková, Zlatko Janeba, Lukas M. Simon, Charles Y. Lin, Monica C. Pillon, Thomas F. Westbrook

Table S2 shows gene ontology analysis of candidate facilitator genes of MYC-induced cell death.

Funding

National Institute of Virology and Bacteriology

Ministry of Education Youth and Sports

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Cancer Prevention and Research Institute of Texas (CPRIT)

National Cancer Institute (NCI)

United States Department of Health and Human Services

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National Institute of Environmental Health Sciences (NIEHS)

United States Department of Health and Human Services

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National Institute of General Medical Sciences (NIGMS)

United States Department of Health and Human Services

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National Institutes of Health (NIH)

Mark Foundation For Cancer Research (The Mark Foundation for Cancer Research)

Susan G. Komen (SGK)

U.S. Department of Defense (DOD)

Welch Foundation (The Welch Foundation)

History

ARTICLE ABSTRACT

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.

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    Cancer Discovery

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    Keywords

    ChemotherapyBiochemical modulators of the therapeutic index

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