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The incidence of prostate cancer (PCa) among African-Americans (AfA) is significantly higher than Caucasian-Americans (CaA) but the genetic basis for this disparity is not known. To address this problem, we analyzed miRNA expression in AfA (n = 81) and CaA (n = 51) PCa patients. Here, we found that miR-24 is differentially expressed in AfA and CaA PCa patients and attempt to clarify its role in AfA patients. Also, the public sequencing data of the miR-24 promoter confirmed that it was highly methylated and down-regulated in PCa patients. Utilizing a VAMCSF and NDRI patient cohorts, we discovered that miR-24 expression was linked to a racial difference between AfA/CaA PCa patients. Interestingly, miR-24 was restored after treatment of PCa cells with 5Aza-CdR in an AfA cell line (MDA-PCa-2b), while restoration of miR-24 was not observed in CaA cells, DU-145. Ectopic expression of miR-24 showed decreased growth and induced apoptosis, though the effect was less in the CaA cell line compared to the AfA cell line. Finally, we found unique changes in biological pathways and processes associated with miR-24 transfected AfA cells by quantitative PCR-based gene expression array. Evaluation of the altered pathways showed that AR, IGF1, IGFBP5 and ETV1 were markedly decreased in the AfA derived cell line compared with CaA cells, and there was a reciprocal regulatory relationship of miR-24/target expression in prostate cancer patients. These results demonstrate that miR-24 may be a central regulator of key events that contribute to race-related tumorigenesis and has potential to be a therapeutic agent for PCa treatment.

// Marisa Shiina 1, * , Yutaka Hashimoto 1, * , Taku Kato 1 , Soichiro Yamamura 1 , Yuichiro Tanaka 1 , Shahana Majid 1 , Sharanjot Saini 1 , Shahryari Varahram 1 , Priyanka Kulkarni 1 , Pritha Dasgupta 1 , Yozo Mitsui 1 , Mitsuho Sumida 1 , Laura Tabatabai 1 , Guoren Deng 1 , Deepak Kumar 2 , Rajvir Dahiya 1 1 Department of Urology, Veterans Affairs Medical Center, San Francisco and University of California San Francisco, San Francisco, California, USA 2 Division of Science and Mathematic, Cancer Research Laboratory, University of the District of Columbia, Washington, DC, USA * These authors have contributed equally to this work Correspondence to: Rajvir Dahiya, email: rdahiya@ucsf.edu Keywords: miR-34b, prostate cancer, african-americans, caucasians, androgen receptor Received: October 04, 2016 Accepted: November 23, 2016 Published: December 25, 2016 ABSTRACT African-Americans are diagnosed with more aggressive prostate cancers and have worse survival than Caucasians, however a comprehensive understanding of this health disparity remains unclear. To clarify the mechanisms leading to this disparity, we analyzed the potential involvement of miR-34b expression in African-Americans and Caucasians. miR-34b functions as a tumor suppressor and has a multi-functional role, through regulation of cell proliferation, cell cycle and apoptosis. We found that miR-34b expression is lower in human prostate cancer tissues from African-Americans compared to Caucasians. DNA hypermethylation of the miR-34b-3p promoter region showed significantly higher methylation in prostate cancer compared to normal samples. We then sequenced the promoter region of miR-34b-3p and found a chromosomal deletion in miR-34b in African-American prostate cancer cell line (MDA-PCA-2b) and not in Caucasian cell line (DU-145). We found that AR and ETV1 genes are differentially expressed in MDA-PCa-2b and DU-145 cells after overexpression of miR-34b. Direct interaction of miR-34b with the 3’ untranslated region of AR and ETV1 was validated by luciferase reporter assay. We found that miR-34b downregulation in African-Americans is inversely correlated with high AR levels that lead to increased cell proliferation. Overexpression of miR-34b in cell lines showed higher inhibition of cell proliferation, apoptosis and G1 arrest in the African-American cells (MDA-PCa-2b) compared to Caucasian cell line (DU-145). Taken together, our results show that differential expression of miR-34b and AR are associated with prostate cancer aggressiveness in African-Americans.

Renal cell carcinoma (RCC) is one of the most common malignancies. Despite the development of therapeutic regimens, the prognosis of patients with RCC is poorly understood. Genistein, a naturally occurring isoflavone, has been reported to have anti-cancer effects on a variety of cancer types. While several studies have shown that genistein inhibits kidney cancer progression in various in vitro and in vivo models, the basic molecular mechanisms of genistein action have not been investigated in kidney cancer. In malignancies, long non-coding RNAs (lncRNAs) are differentially expressed in various tissues and have important functions in cell proliferation, motility and apoptosis. HOX transcript antisense RNA (HOTAIR) is a lncRNA localized in the Homeobox C gene cluster on chromosome 12. HOTAIR is necessary to target the polycomb repressive complex 2 (PRC2) in trans to the HOXD locus and can interacts with (PRC2, which enhances H3K27 trimethylation and represses the expression of tumor suppressors. HOTAIR is highly expressed in various cancers and involved in their progression and metastasis. In our study, we investigated the molecular mechanisms of genistein action through a novel pathway that represses HOTAIR. We found that HOTAIR expression is higher in renal cancer cell lines compared to normal controls. Genistein treatment was found to significantly decrease HOTAIR expression in renal carcinoma cell lines (786-O and ACHN cells). Genistein treatment also reduced expression of epithelial-to-mesenchyme transition (EMT)-related proteins, causing reduced cell migration, invasion, and increased apoptosis. We performed RNA immunoprecipitation assays, and found that genistein inhibits HOTAIR binding to PRC2. One of the other EMT markers, a tight junction protein ZO-1, is upregulated by genistein. We further investigated whether genistein represses PRC2 recruitment to the ZO-1 promoter by inhibiting binding of HOTAIR to PRC2. In this study, we revealed detailed mechanism of antitumor action of genistein. These insights indicate that genistein is a potent therapeutic agent not only for renal cancer but also for a broad spectrum of cancers. Citation Format: Mitsuho I. Sumida, Yuichiro Tanaka, Rajvir Dahiya, Soichiro Yamamura. Genistein regulates non-coding RNA HOTAIR and epithelial-to-mesenchyme transition in renal cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4430.

African-Americans are diagnosed with more aggressive prostate cancers and have worse survival than Caucasians, however a comprehensive understanding of this health disparity remains unclear. To clarify the mechanisms leading to this disparity, we analyzed the potential involvement of miR-34b expression in African-Americans and Caucasians. We found that miR-34b expression is lower in human prostate cancer tissues from African-Americans compared to Caucasians. DNA hypermethylation of the miR-34b-3p promoter region showed significantly higher methylation in prostate cancer compared to normal tissues. We found that AR and ETV1 genes are differentially expressed in MDA-PCa-2b and DU-145 cells after overexpression of miR-34b. Direct interaction of miR-34b with the 3’ untranslated region of AR and ETV1 was validated by luciferase reporter assay. We found that miR-34b downregulation in African-Americans is inversely correlated with high AR levels that lead to increased cell proliferation. Overexpression of miR-34b in cell lines showed higher inhibition of cell proliferation, apoptosis and G1 arrest in African-American cells (MDA-PCa-2b) compared to the Caucasian cell line (DU-145). Taken together, our results show that differential expression of miR-34b and AR are associated with prostate cancer aggressiveness in African-Americans. Citation Format: Marisa Shiina, Yutaka Hashimoto, Taku Kato, Soichiro Yamamura, Yuichiro Tanaka, Shahana Majid, Sharanjot Saini, Shahryari Varahram, Priyanka Kulkarni, Prita Dasgupta, Mitsuho Sumida, Guoren Deng, Rajvir Dahiya. Differential expression of miR-34b and androgen receptor pathway regulate prostate cancer aggressiveness between African Americans and Caucasians [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 483. doi:10.1158/1538-7445.AM2017-483

The incidence of prostate cancer (PCa) among African-Americans (AfA) is significantly higher than Caucasian-Americans (CaA) but the genetic basis for this disparity is not known. To address this problem, we analyzed miRNA expression in AfA (n=81) and CaA (n=51) PCa patients. Here, we found that miR-24 is differentially expressed in AfA and CaA PCa patients and attempt to clarify its role in AfA patients. Also, the public sequencing data of the miR-24 promoter confirmed that it was highly methylated and down-regulated in PCa patients. Utilizing a VAMCSF and NDRI patient cohorts, we discovered that miR-24 expression was linked to a racial difference between AfA/CaA PCa patients. Interestingly, miR-24 was restored after treatment of PCa cells with 5Aza-CdR in an AfA cell line (MDA-PCa-2b), while restoration of miR-24 was not observed in CaA cells, DU-145. Ectopic expression of miR-24 showed decreased growth and induced apoptosis, though the effect was less in the CaA cell line compared to the AfA cell line. Finally, we found unique changes in biological pathways and processes associated with miR-24 transfected AfA cells by quantitative PCR-based gene expression array. Evaluation of the altered pathways showed that AR, PDPK1, IGF1, and IGFBP5 were markedly decreased in the AfA derived cell line compared with CaA cells, and there was a reciprocal regulatory relationship of miR-24/target expression in prostate cancer patients. These results demonstrate that miR-24 may be a central regulator of key events that contribute to race-related tumorigenesis and has potential to be a therapeutic agent for PCa treatment. Citation Format: Yutaka Hashimoto, Marisa Shiina, Taku Kato, Soichiro Yamamura, Yuichiro Tanaka, Shahana Majid, Sharanjot Saini, Varahram Shahryari, Priyanka Kulkarni, Pritha Dasgupta, Yozo Mitsui, Mitsuho Sumida, Guoren Deng, Laura Tabatabai, Deepak Kumar, Rajvir Dahiya. The role of miR-24 as a race-related genetic factor in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 462. doi:10.1158/1538-7445.AM2017-462