| 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. © 2023 The Author(s) |
| Keywords: |
genetics; mutation; nonhistone protein; chromosomal proteins, non-histone; prostate cancer; prostatic neoplasms; cytidine deaminase; prostate tumor; androgen receptor; receptors, androgen; bmi1 protein; mutagenesis; minor histocompatibility antigens; tumor heterogeneity; minor histocompatibility antigen; heterogeneous nuclear ribonucleoprotein; heterogeneous-nuclear ribonucleoproteins; ep300; humans; human; male; foxa1; apobec; apobec3b protein, human; antiandorgen; ar-targeted therapy resistance; syncrip; polycomb repressive complex 1; brd7 protein, human; cbx8 protein, human; syncrip protein, human
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