Abstract B061: Mechanistic and functional interrogation of novel ancestry-related alternatively spliced androgen receptor signal genes in prostate cancer
Onyenwoke, RU; Freedman, JA; Patierno, BM; Eze, C; Dayo, A; George, DJ; Patierno, SR
Published in: Cancer Epidemiology, Biomarkers & Prevention
The age-adjusted incidence and mortality rates for prostate cancer (PCa) among African American (AA) men are significantly higher than among white men. Our studies address the urgent need to interrogate and modulate, for therapeutic application, the molecular mechanisms underlying the more aggressive PCa biology in AA men. The Duke Cancer Institute (DCI) has identified novel alternatively spliced genes between PCa from AA and white patients that drive race-related PCa aggressiveness and drug response, including androgen receptor (AR) target genes. In parallel, North Carolina Central University (NCCU) has interrogated AMP-activated protein kinase (AMPK) signaling, which operates in a regulatory loop with AR, and seeks to target AMPK for therapeutic application. Within the context of the AR/AMPK signaling axis, we have delineated the structures of race-related alternative splicing events in fatty acid synthase (FASN) and six-transmembrane epithelial antigen of the prostate, family member 4 (STEAP4) using polymerase chain reaction and generated CRISPR-Cas constructs to specifically express these variants. In addition, from our exon array analysis, we have identified differential splicing of a cancer-specific ubiquitin ligase complex (MAGE-A3/6-TRIM28), which targets AMPK for degradation, between PCa from AA and white patients. Moreover, we have shown that a PCa cell line derived from an AA patient has a decreased expression level of AMPKα and increased expression levels of TRIM28 splice variants using Western blot. Studies to assess the effects of expression of race-related FASN and STEAP4 variants on PCa cell biology and to directly dissect race-related mechanistic differences in AMPK signaling biology are currently under way. This work identifies and delineates novel AR/AMPK signaling pathway splice variants that may be targetable for PCa.Citation Format: Rob U. Onyenwoke, Jennifer A. Freedman, Brendon M. Patierno, Cedric Eze, Adepeju Dayo, Daniel J. George, Steven R. Patierno. Mechanistic and functional interrogation of novel ancestry-related alternatively spliced androgen receptor signal genes in prostate cancer [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr B061.
