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

Autor:	Meena JK; Therapeutic Innovation Center (THINC), Baylor College of Medicine, Houston, Texas.; Verna & Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, Texas., Wang JH; Verna & Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, Texas.; Medical Scientist Training Program, Baylor College of Medicine, Houston, Texas., Neill NJ; Therapeutic Innovation Center (THINC), Baylor College of Medicine, Houston, Texas.; Verna & Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, Texas.; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas., Keough D; The School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Australia., Putluri N; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas., Katsonis P; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas., Koire AM; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas., Lee H; Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Bowling EA; Therapeutic Innovation Center (THINC), Baylor College of Medicine, Houston, Texas.; Verna & Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, Texas., Tyagi S; Verna & Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, Texas., Orellana M; Verna & Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, Texas., Dominguez-Vidaña R; Verna & Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, Texas., Li H; Verna & Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, Texas., Eagle K; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas., Danan C; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas., Chung HC; Verna & Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, Texas., Yang AD; Therapeutic Innovation Center (THINC), Baylor College of Medicine, Houston, Texas.; Verna & Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, Texas.; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.; Medical Scientist Training Program, Baylor College of Medicine, Houston, Texas., Wu W; Verna & Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, Texas.; Medical Scientist Training Program, Baylor College of Medicine, Houston, Texas., Kurley SJ; Verna & Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, Texas., Ho BM; Verna & Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, Texas.; Medical Scientist Training Program, Baylor College of Medicine, Houston, Texas., Zoeller JR; Therapeutic Innovation Center (THINC), Baylor College of Medicine, Houston, Texas.; Verna & Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, Texas.; Medical Scientist Training Program, Baylor College of Medicine, Houston, Texas., Olson CM; Therapeutic Innovation Center (THINC), Baylor College of Medicine, Houston, Texas.; Verna & Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, Texas., Meerbrey KL; Therapeutic Innovation Center (THINC), Baylor College of Medicine, Houston, Texas.; Verna & Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, Texas., Lichtarge O; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas., Sreekumar A; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas., Dacso CC; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas., Guddat LW; The School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Australia., Rejman D; Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague, Czech Republic., Hocková D; Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague, Czech Republic., Janeba Z; Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague, Czech Republic., Simon LM; Therapeutic Innovation Center (THINC), Baylor College of Medicine, Houston, Texas., Lin CY; Therapeutic Innovation Center (THINC), Baylor College of Medicine, Houston, Texas.; Verna & Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, Texas.; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas., Pillon MC; Therapeutic Innovation Center (THINC), Baylor College of Medicine, Houston, Texas.; Verna & Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, Texas., Westbrook TF; Therapeutic Innovation Center (THINC), Baylor College of Medicine, Houston, Texas.; Verna & Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, Texas.; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas.
Jazyk:	angličtina
Zdroj:	Cancer discovery [Cancer Discov] 2024 Sep 04; Vol. 14 (9), pp. 1699-1716.
DOI:	10.1158/2159-8290.CD-22-0649
Abstrakt:	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. (©2024 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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