Abstract 251: Luteolin-mediated increase in miR-26a inhibits prostate cancer cell growth and induces cell cycle arrest targeting EZH2

Abstract

Abstract Luteolin (3',4',5,7-tetrahydroxyflavone), a flavonoid found in several vegetables and fruits, has been reported to possess anticancer and apoptosis inducing properties. However, the molecular targets of luteolin action are presently unknown. The enhancer of zeste homolog 2 (EZH2) is a catalytic subunit of polycomb repressive complex 2 (PRC2), which catalyzes the trimethylation of histone H3 on Lysine 27 (H3K27) and is involved in chromatin remodeling and gene silencing. EZH2-mediated epigenetic gene silencing plays an important role in several human cancers including prostate neoplasm. Emerging studies demonstrate that miR-26a, a non-coding microRNA, regulates EZH2 expression and is frequently lost during cancer progression. Here we investigated the potential involvement of luteolin-mediated miR-26a upregulation and EZH2 suppression leading to cell cycle arrest and apoptosis in cancer cells. Human prostate cancer DU145 and PC-3 cells, which possess high constitutive EZH2 expression, were treated with 5-20 µM luteolin at various times significantly inhibited EZH2 and H3K27 trimethylation in dose and time dependent manner. Luteolin treatment further resulted in increased expression of miR-26a in both cell lines, as exhibited by EZH2 inhibitor GSK126. Mechanistic investigations revealed that miR-26a overexpression suppressed cell cycle regulatory molecules such as cyclin D and E, cyclin dependent kinases CDK4 and CDK6, and CDK inhibitors p14/ARF, p16/INK4A and p21/WAF1 in EZH2-dependent manner. Interestingly, similar observations were noted in prostate cancer cells with a marked decrease in cyclins and CDKs along with concomitant increase in CDK inhibitors after luteolin treatment resulting in G0/G1 phase cell cycle arrest. In plasma specimens, obtained from healthy individuals, high-risk subjects and prostate cancer patients exhibit a progressive decrease in miR-26a expression. Taken together, our results indicate that miR-26a functions as a growth suppressive miRNA lost in prostate cancer, whereas luteolin is a promising agent which demonstrate anti-proliferative effects mediated by upregulation of miR-26 repressing EZH2 in prostate cancer cells. Citation Format: Rajnee Kanwal, Stephen Moreton, Daniel Franco, Sanjay Gupta. Luteolin-mediated increase in miR-26a inhibits prostate cancer cell growth and induces cell cycle arrest targeting EZH2 [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 251.