Androgen Receptor (AR) antagonism is exacerbated by HOXB13 in Castration Resistant Prostate Cancers (CRPCs). However, it is unclear when and how does HOXB13 prime CRPCs for AR antagonism. By mass-spectrometry analysis of CRPC extract we uncovered a novel lysine 13 (K13) acetylation in HOXB13 mediated by CBP/p300. To determine whether acetylated K13-HOXB13 is a clinical biomarker of CRPC development, we characterized its role in prostate cancer biology.
We identified tumor-specific acK13-HOXB13 signal enriched Super enhancer (SE) regulated targets. We analyzed the effect of loss of HOXB13K13-acetylation on chromatin binding, SE proximal target gene expression, self-renewal, enzalutamide sensitivity and CRPC tumor growth employing isogenic parental and HOXB13K13A mutants. Finally, using primary human prostate organoids we evaluated whether inhibiting an acK13-HOXB13 target, ACK1, with a selective inhibitor (R)-9b is superior to AR antagonists in inhibiting CRPC growth.
acK13-HOXB13 promotes increased expression of lineage (AR, HOXB13), PC diagnostic (FOLH1) CRPC-promoting (ACK1) and angiogenesis (VEGFA, Angiopoietins) genes early in PC development by establishing tumor-specific SEs. acK13-HOXB13 recruitment to key SE regulated targets is insensitive to Enzalutamide. ACK1 expression is significantly reduced in the loss of function HOXB13K13A mutant CRPCs. Consequently, HOXB13K13A mutants display reduced self-renewal, increased sensitivity to enzalutamide and impaired xenograft tumor growth. Primary human prostate tumor organoids expressing HOXB13 are significantly resistant to AR antagonists but sensitive to (R)-9b.
In summary, acetylated HOXB13 is a biomarker of clinically significant PC. Importantly, PSMA-targeting agents and (R)-9b could be new therapeutic modalities to target HOXB13-ACK1 axis regulated PCs.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2022 Jul 18 [Epub ahead of print]
Duy T Nguyen, Wei Yang, Arun Renganathan, Cody Weimholt, Duminduni H Angappulige, Thanh Nguyen, Robert W Sprung, Gerald L Andriole, Eric H Kim, Nupam P Mahajan, Kiran Mahajan
Washington University in St. Louis, St. Louis, MO, United States., Washington University in St. Louis School of Medicine, United States., Moffitt Cancer Center, St. Louis, MO, United States., Washington University in St. Louis, St.Louis, MO, United States., Johns Hopkins University School of Medicine, Baltimore, MD, United States.