Prostate-specific membrane antigen (PSMA) is an important cell surface target in prostate cancer. There are limited data on the heterogeneity of PSMA tissue expression in metastatic castration-resistant prostate cancer (mCRPC). Furthermore, the mechanisms regulating PSMA expression (encoded by the FOLH1 gene) are not well understood. Here, we demonstrate that PSMA expression is heterogeneous across different metastatic sites and molecular subtypes of mCRPC. In a rapid autopsy cohort in which multiple metastatic sites per patient were sampled, we found that 13/52 (25%) cases had no detectable PSMA and 23/52 (44%) showed heterogeneous PSMA expression across individual metastases with 33 (63%) cases harboring at least one PSMA-negative site. PSMA-negative tumors displayed distinct transcriptional profiles, including the expression of druggable targets such as MUC1. Loss of PSMA was associated with epigenetic changes of the FOLH1 locus, including gain of CpG methylation and loss of histone 3 lysine 27 (H3K27) acetylation. Treatment with histone deacetylase (HDAC) inhibitors reversed this epigenetic repression and restored PSMA expression in vitro and in vivo. Collectively, these data provide novel insights into the expression patterns and regulation of PSMA in mCRPC and suggest that epigenetic therapies, in particular HDAC inhibitors, can be used to augment PSMA levels.
JCI insight. 2023 Feb 23 [Epub ahead of print]
Erolcan Sayar, Radhika A Patel, Ilsa M Coleman, Martine P Roudier, Ailin Zhang, Pallabi Mustafi, Jin-Yih Low, Brian Hanratty, Lisa S Ang, Vipul Bhatia, Mohamed Adil, Hasim Bakbak, David A Quigley, Michael T Schweizer, Jessica E Hawley, Lori Kollath, Lawrence D True, Felix Y Feng, Neil H Bander, Eva Corey, John K Lee, Colm Morrissey, Roman Gulati, Peter S Nelson, Michael C Haffner
Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, United States of America., Department of Urology, University of Washington, Seattle, United States of America., Comprehensive Cancer Center, University of California, San Francisco, San Francisco, United States of America., Medical Oncology, University of Washington, Seattle, United States of America., Department of Laboratory Medicine and Pathology, University of Washington, Seattle, United States of America., Department of Urology, Weill Cornell Medical College, New York, United States of America., Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, United States of America., Division of Nephrology, University of Washington, Seattle, United States of America.