Language
English
Publication Date
10-12-2023
Journal
bioRxiv
DOI
10.1101/2023.09.28.560025
PMID
37905039
PMCID
PMC10614109
PubMedCentral® Posted Date
10-12-2023
PubMedCentral® Full Text Version
Pre-Print
Abstract
Androgen receptor- (AR-) indifference is a mechanism of resistance to hormonal therapy in prostate cancer (PC). Here we demonstrate that the HOX/CUT transcription factor ONECUT2 (OC2) activates resistance through multiple drivers associated with adenocarcinoma, stem-like and neuroendocrine (NE) variants. Direct OC2 targets include the glucocorticoid receptor and the NE splicing factor SRRM4, among others. OC2 regulates gene expression by promoter binding, enhancement of chromatin accessibility, and formation of novel super-enhancers. OC2 also activates glucuronidation genes that irreversibly disable androgen, thereby evoking phenotypic heterogeneity indirectly by hormone depletion. Pharmacologic inhibition of OC2 suppresses lineage plasticity reprogramming induced by the AR signaling inhibitor enzalutamide. These results demonstrate that OC2 activation promotes a range of drug resistance mechanisms associated with treatment-emergent lineage variation in PC. Our findings support enhanced efforts to therapeutically target this protein as a means of suppressing treatment-resistant disease.
Published Open-Access
yes
Recommended Citation
Qian, Chen; Yang, Qian; Rotinen, Mirja; et al., "ONECUT2 Activates Diverse Resistance Drivers of Androgen Receptor-Independent Heterogeneity in Prostate Cancer" (2023). Faculty, Staff and Students Publications. 8113.
https://digitalcommons.library.tmc.edu/baylor_docs/8113