TY - JOUR
T1 - Acetylated HOXB13 Regulated Super Enhancer Genes Define Therapeutic Vulnerabilities of Castration-Resistant Prostate Cancer
AU - Nguyen, Duy T.
AU - Yang, Wei
AU - Renganathan, Arun
AU - Weimholt, Cody
AU - Angappulige, Duminduni H.
AU - Nguyen, Thanh
AU - Sprung, Robert W.
AU - Andriole, Jerry
AU - Kim, Eric H.
AU - Mahajan, Nupam P.
AU - Mahajan, Kiran
N1 - Funding Information:
N.P. Mahajan reports grants from NIH/NCI, Prostate Cancer Foundation, and Department of Defense during the conduct of the study, as well as other support from TechnoGenesys, Inc. outside the submitted work; N.P. Mahajan also has patents 9,850,216 and 10,017,47 issued and licensed to TechnoGenesys, Inc. K. Mahajan reports grants from Department of Defense, NCATS Clinical and Translational Sciences Award, Siteman Comprehensive Cancer Center Support Grant, and Phi Beta Psi Sorority during the conduct of the study, as well as other support from Technogenesys outside the submitted work; K. Mahajan also has a patent for WU Reference: T-019682 pending. No disclosures were reported by the other authors.
Funding Information:
K. Mahajan acknowledges support from the Phi Beta Psi Sorority, Department of Defense W81XWH-21-1-0203, NCATS Clinical and Translational Sciences Award, #UL1 TR002345, and the Department of Surgery at Washington University. N.P. Mahajan is a recipient of NIH/NCI grants (1R01CA208258 and 5R01CA227025), Prostate Cancer Foundation (PCF) grant (17CHAL06) and Department of Defense grant (W81XWH-21-1-0202). The WU-PSR is supported in part by the WU Institute of Clinical and Translational Sciences (NCATS UL1 TR000448), the Mass Spectrometry Research Resource (NIGMS P41 GM103422; R24GM136766), and the Siteman Comprehensive Cancer Center Support Grant (NCI P30 CA091842). The Siteman Cancer Center is supported in part by an NCI Cancer Center Support Grant No. P30 CA091842.
Publisher Copyright:
© 2022 American Association for Cancer Research.
PY - 2022/9/15
Y1 - 2022/9/15
N2 - Purpose: Androgen receptor (AR) antagonism is exacerbated by HOXB13 in castration-resistant prostate cancers (CRPC). However, it is unclear when and how HOXB13 primes 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. Experimental Design: 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 by employing isogenic parental andHOXB13K13A 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. Results: acK13-HOXB13 promotes increased expression of lineage (AR, HOXB13), prostate cancer diagnostic (FOLH1), CRPC-promoting (ACK1), and angiogenesis (VEGFA,Angiopoietins) genes early in prostate cancer development by establishing tumorspecific 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. Conclusions: In summary, acetylated HOXB13 is a biomarker of clinically significant prostate cancer. Importantly, PSMA-targeting agents and (R)-9b could be new therapeutic modalities to target HOXB13-ACK1 axis regulated prostate cancers.
AB - Purpose: Androgen receptor (AR) antagonism is exacerbated by HOXB13 in castration-resistant prostate cancers (CRPC). However, it is unclear when and how HOXB13 primes 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. Experimental Design: 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 by employing isogenic parental andHOXB13K13A 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. Results: acK13-HOXB13 promotes increased expression of lineage (AR, HOXB13), prostate cancer diagnostic (FOLH1), CRPC-promoting (ACK1), and angiogenesis (VEGFA,Angiopoietins) genes early in prostate cancer development by establishing tumorspecific 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. Conclusions: In summary, acetylated HOXB13 is a biomarker of clinically significant prostate cancer. Importantly, PSMA-targeting agents and (R)-9b could be new therapeutic modalities to target HOXB13-ACK1 axis regulated prostate cancers.
UR - http://www.scopus.com/inward/record.url?scp=85138446952&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-21-3603
DO - 10.1158/1078-0432.CCR-21-3603
M3 - Article
C2 - 35849143
AN - SCOPUS:85138446952
SN - 1078-0432
VL - 28
SP - 4131
EP - 4145
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 18
ER -