Steroidogenic Factor 1 Promotes Aggressive Growth of Castration-Resistant Prostate Cancer Cells by Stimulating Steroid Synthesis and Cell Proliferation

Abstract

The dependence of prostate cancer on androgens provides a targeted means of treating advanced disease. Unfortunately, androgen deprivation therapies eventually become ineffective, leading to deadly castration-resistant prostate cancer (CRPC). One of many factors implicated in the transition to CRPC is the onset of de novo steroidogenesis. Although reactivation of steroid receptors likely plays a pivotal role in aggressive CRPC, little is understood regarding the mechanisms whereby prostate cancer cells initiate and maintain steroidogenesis. We hypothesize that steroidogenic factor 1 (SF1, NR5A1, AD4BP), a key regulator of steroidogenesis in normal endocrine tissues, is expressed in CRPC where it stimulates aberrant steroidogenesis and fuels aggressive growth. Notably, SF1 is not expressed in normal prostate tissue. Our results indicated that SF1 was absent in benign cells but present in aggressive prostate cancer cell lines. Introduction of ectopic SF1 expression in benign human prostate epithelial cells (BPH-1) stimulated increased steroidogenic enzyme expression, steroid synthesis, and cell proliferation. In contrast, data from an aggressive human prostate cancer cell line (BCaPT10) demonstrated that SF1 was required for steroid-mediated cell growth because BCaPT10 cell growth was diminished by abiraterone treatment and short hairpin RNA-mediated knockdown of SF1 (shSF1). SF1-depleted cells also exhibited defective centrosome homeostasis. Finally, whereas xenograft experiments in castrated hosts with BCaPT10 control transplants grew large, invasive tumors, BCaPT10-shSF1 knockdown transplants failed to grow. Therefore, we conclude that SF1 stimulates steroid accumulation and controls centrosome homeostasis to mediate aggressive prostate cancer cell growth within a castrate environment. These findings present a new molecular mechanism and therapeutic target for deadly CRPC.

DNA methylation screening of primary prostate tumors identifies SRD5A2 and CYP11A1 as candidate markers for assessing risk of biochemical recurrence

“…While healthy individuals have very low cfDNA amount in the plasma, cancer patients tend to have increased levels of cfDNA and patients with more aggressive and/or metastatic cancer have even higher levels of plasma‐derived cfDNA . Studies have shown that the blood of cancer patients contains cfDNA that matches specific DNA mutations and chromosomal translocations originally present in primary tumors . In our case, we found that increased methylation of SRD5A2 and CYP11A1 detected in primary tumors can also be validated in plasma‐derived cfDNA of separate PCa patients.…”

Conditional deletion of ELL2 induces murine prostate intraepithelial neoplasia

“…qPCR validation confirmed the persistent altered expression of several of these genes in animals at 17 mos of age, including Sfi1 , Cxcl10 , Pds5a , Rtn4 , Olig2 , Rhobtb3 , and Gbp2 suggesting that these genes and their associated pathways might contribute to the development of the histological defects identified in the prostates of aged animals with ELL2 loss. SFI1 is a key regulator of normal endocrine steroidogenesis, which is up-regulated in castration resistant prostate cancer (Lewis, et al 2014). PDS5A, also known as SCC-112, was recently reported as a translocation partner of MLL (Put, et al 2012) and was initially characterized as a cell cycle regulator and promoter of apoptosis (Kumar, et al 2004).…”

Interplay among transcription factors Ets21c, Fos and Ftz-F1 drives JNK-mediated tumor malignancy

“…While FLI1 is considered pivotal to development of Ewing's sarcoma ( May et al, 1993 ), ERG has been linked to leukemia and prostate cancer ( Yi et al, 1997 ; Petrovics et al, 2005 ). As for Ftz-F1 orthologs, the human liver receptor homolog-1 (LRH-1) has been associated with colonic, gastric, breast and pancreatic cancer ( Annicotte et al, 2005 ; Schoonjans et al, 2005 ; Wang et al, 2008 ; Benod et al, 2011 ), whereas steroidogenic factor 1 (SF-1) has been implicated in prostate and testicular cancers ( Straume et al, 2012 ; Lewis et al, 2014 ) and in adrenocortical carcinoma ( Doghman et al, 2007 ). However, the molecular mechanisms underlying oncogenic activities of either the ERG/FLI1 or the SF-1/LRH-1 proteins are not well understood.…”