Prostate cancer (PCa) remains a leading cause of cancer deaths because many patients ultimately develop an incurable castration-resistant form of metastatic PCa. While chromatin alterations are linked to PCa, the role of histone demethylases in the PCa progression has not been fully elucidated. Members of the Jumonji AT-rich interactive domain 1 (JARID1) or lysine demethylase 5 (KDM5) family of lysine demethylases are known for their ability to demethylate H3K4me3. However, the genes encoding these proteins are amplified in metastatic PCa. Literature suggests members of the KDM5 family enhance expression and function of androgen receptor (AR), a protein that drives growth of human PCa cells. The KDM5 family inhibitor 2-4(4-methylphenyl)-1,2-benzisothiazol-3(2H)-one (PBIT) has been suggested as a potential lead compound for cancer therapy since it suppresses proliferation of human breast cancer cells. However, to date no studies have tested the effects of PBIT in PCa. The goal of this study was to characterize the effects of PBIT alone and in combination with a PPARγ agonist, 15-Deoxy-Δ-12,14-prostaglandin J2 (15-dPGJ2) on PCa cells. Presto blue analyses were conducted in AR positive, castration-sensitive LNCaP cells and the castration-resistant PC3 cells expressing little to no AR. Our studies revealed that PBIT treatment decreased the proliferation of both LNCaP and PC3 cells in a dose-dependent manner. Significant decreases in cell proliferation were detected when PBIT concentrations were greater than or equal to 5 μM. In addition, 15-dPGJ2 was able to decrease the proliferation of PCa cells. Importantly, the combination of PBIT and 15-dPGJ2 significantly suppressed the growth of PC3 and LNCaP cells. The anti-proliferative effect of the combined inhibition was at least additive, as the combination index was less than 1. Furthermore, PBIT at concentrations ≥ 5 μM also reduced migration of PC3 cells. Together, our data suggest that PBIT and other KDM5 inhibitors can reduce the proliferation and migration of multiple types of PCa cells. Our findings also provide evidence that the combination of KDM5 family inhibitors and PPARγ agonists might serve as an effective therapy for advanced human PCa.
Citation Format: Tunde Smith, Zhenbang Chen, LaMonica V. Stewart. KDM5 inhibitor regulates growth of early stage and advanced human prostate cancer cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1759.