Abstract 5213: microRNA-mediated loss of KDM5B expression leads to suppression of the malignant bladder cancer phenotype

Abstract

We recently identified KDM5B as a putative oncogene. The expression of KDM5B correlated with increased cellular proliferative capacity and was found to be overexpressed in many cancers including bladder cancer (BC). KDM5B is a histone demethylase enzyme that modifies chromatin structure to specify cellular transcriptional states. It is a cancer/testis antigen; whereby in normal conditions, expression is limited to early embryonic stages and the testis in adults. Thus, KDM5B is an excellent therapeutic target. Since the expression of KDM5B in embryonic stem cells is orchestrated by miRNAs and that the expression of miRNAs are altered in BC, we hypothesized that miRNAs may be the switch that can abate the expression of KDM5B and thus affect the malignant phenotype of BC cells. This study was aimed at identifying and modulating the expression of miRNAs that are able to regulate KDM5B expression and BC phenotypes. By coupling in silico screens with RT-QPCR analysis of in vitro expression of BC cells of different malignant potential, we predicted several miRNAs as potential regulators of KDM5B transcripts. The functional effects of specific miRNAs on KDM5B expression, cell cycle, proliferation and invasion of BC cells was determined by modulating the expression of these miRNAs using mimics (upregulation) and antagomirs (downregulation). Expression of miR-137 in BC cells was found to be inversely correlated with KDM5B expression. Ectopic overexpression of miR-137 led to the repression of KDM5B expression, reduced cell growth and invasion as well as increased apoptosis of BC cells. In contrast, the downregulation of miR-137 expression led to reverse effects. The expression modulation of miR-137 also affected the expression of other BC-associated genes such as JDP2 and EGR2. While our results suggest that miR-137 can mitigate the KDM5B-associated BC phenotype, further studies on understanding the effect on aberrant histone methylation patterns are warranted. Citation Format: Abhimanyu Veerakumarasivam, Radha Kodiappan, Soon Choy Chan, Azad Hassan Abdul Razack, Teng Aik Ong. microRNA-mediated loss of KDM5B expression leads to suppression of the malignant bladder cancer phenotype. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5213. doi:10.1158/1538-7445.AM2014-5213

Expression and clinical significance of KDM5A, KDM5B, and FOXO1 in endometrial cancer

“…In oral squamous cell carcinoma, KDM5B can induce the transformation of the stem cell-like cell population in cancer between different states and inhibit cell migration and invasion [49]. Ectopic overexpression of miR-137 can inhibit the expression of KDM5B, reduce cell growth and invasion, and increase the apoptosis of bladder cancer cells [50]. In cervical squamous cell carcinoma, KDM5B is down-regulated to inhibit members of the Bcl-2 family, ultimately leading to G1 phase suppression and early apoptosis [51].…”