Faculty, Staff and Student Publications
Publication Date
8-14-2023
Journal
Cancer Cell
Abstract
Tumor mutational burden and heterogeneity has been suggested to fuel resistance to many targeted therapies. The cytosine deaminase APOBEC proteins have been implicated in the mutational signatures of more than 70% of human cancers. However, the mechanism underlying how cancer cells hijack the APOBEC mediated mutagenesis machinery to promote tumor heterogeneity, and thereby foster therapy resistance remains unclear. We identify SYNCRIP as an endogenous molecular brake which suppresses APOBEC-driven mutagenesis in prostate cancer (PCa). Overactivated APOBEC3B, in SYNCRIP-deficient PCa cells, is a key mutator, representing the molecular source of driver mutations in some frequently mutated genes in PCa, including FOXA1, EP300. Functional screening identifies eight crucial drivers for androgen receptor (AR)-targeted therapy resistance in PCa that are mutated by APOBEC3B: BRD7, CBX8, EP300, FOXA1, HDAC5, HSF4, STAT3, and AR. These results uncover a cell-intrinsic mechanism that unleashes APOBEC-driven mutagenesis, which plays a significant role in conferring AR-targeted therapy resistance in PCa.
Keywords
Male, Humans, Mutagenesis, Mutation, Prostatic Neoplasms, Receptors, Androgen, Chromosomal Proteins, Non-Histone, Heterogeneous-Nuclear Ribonucleoproteins, Cytidine Deaminase, Minor Histocompatibility Antigens, Polycomb Repressive Complex 1, APOBEC, AR-targeted therapy resistance, EP300, FOXA1, SYNCRIP, antiandorgen, mutagenesis, prostate cancer, tumor heterogeneity.
DOI
10.1016/j.ccell.2023.06.010
PMID
37478850
PMCID
PMC10530398
PubMedCentral® Posted Date
9-27-2023
PubMedCentral® Full Text Version
Author MSS
Graphical Abstract
Published Open-Access
yes
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