Project description:Prostate cancer (PCa) is the second most lethal cancer in men in the United States. African American (AA) men have twice the incidence and death rate from the disease than European American (EA) men. Early-stage PCa is treated with hormone deprivation therapy, although patients frequently experience relapse. Advanced stage PCa is associated with increased expression and activity of the DNA damage/repair pathway enzyme, poly (ADP-ribose) polymerase 1 (PARP1). Furthermore, PARP1 inhibitors are FDA-approved for the treatment of advanced PCa tumors that carry mutations in components of a specific DNA damage/repair pathway termed homologous recombination repair (HRR). However, PARPi also provide benefit in model systems without HRR incompetencies. A number of different PARPi have now been developed, tested and approved for use in PCa. These inhibitors utilize multiple biochemical mechanisms of action and exhibit distinct potencies and toxicity profiles. While there is emerging evidence of differences in DNA damage/repair pathway enzyme expression between EA and AA men, PARP1 itself has not been fully explored in the context of race. This study hypothesized that 1) AA and EA PCa may respond differently to PARPi and 2) different PARPi may differentially impact the transcriptome, irrespective of HRR status. To test these hypotheses, PCa patient samples from a racially diverse cohort were examined to define race-based differences in PARP activity/expression. Additionally, biologically relevant doses of five clinically relevant PARPi were established across multiple PCa lines carrying different genetic backgrounds, HRR status, and hormone therapy sensitivities. Collectively, these findings demonstrate a link between racial background and PARP1 expression/activity and define a core transcriptional response that lies downstream of all five PARPi, while simultaneously defining transcriptional programs unique to each inhibitor. These findings broaden our understanding of the effector pathways downstream of individual PARPi and provide a compelling rationale for a broader exploration of the impact of race on the response to PARPi. They may also help refine personalized recommendations for use of specific PARPi.

Project description:Prostate cancer incidence and related mortality are disproportionately higher in African American (AA) men than European American (EA) men, but the molecular mechanisms contributing to racial disparities are not fully elucidated. To identify molecular factors that can contribute to disease biology in prostate cancer from AA and EA men, we utilized a multi-omics approach to measure and integrate DNA methylation with gene expression changes. We compared and contrasted results from adjacent non-tumor and tumor tissues from AA and EA men. We found that hypermethylated regions are enriched for PRC2 and H3K27me3 pathways and EZH2/SUZ12 cofactors in a race-independent manner. On the other hand, hypomethylated regions in prostate tumors from AA men were enriched for olfactory/ribosomal pathways as well as distinct cofactors such as CTCF and KMT2A. DNA methylation at transcription start sites and 5’-UTR at GATA3, an androgen receptor (AR) coregulator, is associated with decreased gene expression in prostate tumors of AA men. Our analysis also showed an inverse correlation between DNA methylation and RNA expression of AR transcriptional targets, such as TRIM63, in prostate tumors of AA men. Our observations suggest a dysregulation of the AR signaling pathway in prostate cancer from AA men. To determine whether targeting AR results in race-specific gene expression changes, we utilized a prostate-cancer-specific Boolean network. Our simulation revealed that prolonged AR inhibition results in significant dysregulation in TGF-β, IDH1, and cell cycle pathways in prostate cancer of AA men. We expanded our observation of gene expression changes in the Boolean network and investigated RNA-sequencing data to better understand overall transcriptional alterations occurring in prostate tumors from AA and EA men. We found that gene expression changes related to microtubules, a subset of immune-related, and TMPRSS2-fusion pathways were dysregulated in prostate tumors of AA men and corresponded with progression-free survival of AA men. Altogether, the current study dissects complex signaling networks that are clinically actionable in prostate cancer from AA and EA men.

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Mechanistic Link Between Glyoxalase 1 Expression and Methylglyoxal-Induced Oncogenic Stress in Prostate Cancer

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