The nuclear matrix protein Scaffold Attachment Factor B1 (SAFB1, SAFB) can act in prostate cancer (PCa) as an androgen receptor (AR) co-repressor that functions through epigenetic silencing of AR targets, such as prostate specific antigen (PSA, KLK3). Genomic profiling of SAFB1-silenced PCa cells indicated that SAFB1 may play a role in modulating intracrine androgen levels through the regulation of UDP-glucuronosyltransferase (UGT) genes, which inactivate steroid hormones. Gene silencing of SAFB1 resulted in increased levels of free dihydrotesterosterone (DHT), and increased resistance to the AR inhibitor enzalutamide. SAFB1 silencing suppressed expression of the UDP-glucuronosyltransferase family 2 member B15 gene (UGT2B15) and the closely related UGT2B17 gene, which encode proteins that irreversibly inactivate testosterone (T) and DHT. Analysis of human data indicated that genomic loss at the SAFB locus, or down-regulation of expression of the SAFB gene, is associated with aggressive PCa. These findings identify SAFB1 as an important regulator of androgen catabolism in PCa and suggest that loss or inactivation of this protein may promote AR activity by retention of active androgen in tumor cells.
American journal of clinical and experimental urology. 2021 Aug 25*** epublish ***
Julie Suan-Wei Yang, Chen Qian, Sungyong You, Mirja Rotinen, Edwin M Posadas, Stephen J Freedland, Dolores Di Vizio, Jayoung Kim, Michael R Freeman
Division of Cancer Biology and Therapeutics, Departments of Surgery and Biomedical Sciences, Cedars-Sinai Medical Center Los Angeles, CA 90048, USA., Department of Health Sciences, Public University of Navarre Pamplona, Spain., Division of Medical Oncology, Department of Medicine, Cedars-Sinai Medical Center Los Angeles, CA 90048, USA.