MYC Induces Oncogenic Stress through RNA Decay and Ribonucleotide Catabolism in Breast Cancer
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F24%3A00597801" target="_blank" >RIV/61388963:_____/24:00597801 - isvavai.cz</a>
Result on the web
<a href="https://doi.org/10.1158/2159-8290.CD-22-0649" target="_blank" >https://doi.org/10.1158/2159-8290.CD-22-0649</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1158/2159-8290.CD-22-0649" target="_blank" >10.1158/2159-8290.CD-22-0649</a>
Alternative languages
Result language
angličtina
Original language name
MYC Induces Oncogenic Stress through RNA Decay and Ribonucleotide Catabolism in Breast Cancer
Original language description
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.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
10401 - Organic chemistry
Result continuities
Project
<a href="/en/project/LX22NPO5103" target="_blank" >LX22NPO5103: National Institute of Virology and Bacteriology</a><br>
Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2024
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Cancer Discovery
ISSN
2159-8274
e-ISSN
2159-8290
Volume of the periodical
14
Issue of the periodical within the volume
9
Country of publishing house
US - UNITED STATES
Number of pages
18
Pages from-to
1699-1716
UT code for WoS article
001305886700009
EID of the result in the Scopus database
2-s2.0-85203302498