Abstract B73: SOX2 regulation of FOXP1 as a mechanism driving disparate aggressiveness of prostate cancer in African-American men

Background: Although organ-confined, moderately graded prostate cancer has encouraging cure rates, progression to castration-resistant prostate cancer (CRPC) from advanced, high-grade lesions represents the lethal form of this malignancy, for which current therapeutic modalities are only palliative; patients with CRPC will die from their disease. Importantly, African-American (AA) men exhibit both a higher incidence of prostate cancer diagnoses and are at higher risk of developing CRPC as compared to other racial groups. Currently, the mechanisms driving prostate cancer disparities in AA men are poorly understood, and new biomarkers and novel drugs to address this disparity are in high demand to improve personalized medicine and clinical management of prostate cancer in AA men. Work by our group and others has identified SOX2 (sex determining region Y-box 2), an essential transcription factor for maintaining the survival and pluripotency of undifferentiated embryonic stem cells (ESCs), to be associated with aggressive prostate cancer and that the constitutive overexpression of SOX2 in a hormone-sensitive, SOX2-negative prostate cancer cell line is sufficient to generate a castration-resistant phenotype both in vitro and in vivo. Further, our data demonstrate canonical SOX2 transcriptional cofactors OCT4 and NANOG are frequently not expressed in prostate cancer, implying that SOX2 has unique, non-stem cell gene targets and binding partners within malignant prostate malignancies. Methods and Results: To elucidate such SOX2 gene targets in CRPC, we performed SOX2 chromatin immunoprecipitation and sequencing (ChIP-Seq) in prostate cancer cells, revealing SOX2 binding of several interesting and functionally important gene target promoters, including FOXP1, an AR target gene and transcription factor known to play a role in disparate aggressiveness of prostate cancer in African-American men. Based on these findings, we hypothesize that upon AR ablation in prostate cancer treatment, FOXP1, a tumor suppressor demonstrated to be associated with disparate prostate cancer aggressiveness in AA men, is repressed by SOX2 to drive CRPC in AA men. Work to test this hypothesis is currently under way, and includes (1) assessment of differential FOXP1 gene expression using MDA-PCa-2a, MDA-PCa-2b, and EA0066-hT, prostate cancer cell lines derived from AA men, and CWRR1, CWR22Rv1, and LNCaP, prostate cancer cell lines derived from CA men overexpressing SOX2 in the context of AR ablation; and (2) FOXP1 ChIP-Seq paired with RNA-Seq in tumor tissues prospectively collected from AA and CA men with prostate cancer undergoing radical prostatectomy. Conclusion: The work proposed herein represents an in-depth exploration of basic SOX2 biology in the context of CRPC, is highly innovative and translational, and has transformative potential to improve clinical patient management and eradicate disparities in CRPC. Note: This abstract was not presented at the conference. Citation Format: Anthony Williams, Larischa de Wet, Marc Gillard, Steve Kregel, Tzintzuni Garcia, Russell Szmulewitz, Don Vander Griend. SOX2 regulation of FOXP1 as a mechanism driving disparate aggressiveness of prostate cancer in African-American men [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr B73.