Targeting USP1‐dependent KDM4A protein stability as a potential prostate cancer therapy. Issue 5 (30th March 2020)

• Record Type: Journal Article
• Authors: Cui, Shu‐Zhong; Lei, Zi‐Ying; Guan, Tian‐Pei; Fan, Ling‐Ling; Li, You‐Qiang; Geng, Xin‐Yan; Fu, De‐Xue; Jiang, Hao‐Wu; Xu, Song‐Hui
• Is Part Of: Cancer science. Volume 111:Issue 5(2020)
• Page Start: 1567
• Page End: 1581
• Publication Date: 2020-03-30
• Subjects: deubiquitination -- KDM4A -- prostate cancer -- tumorigenesis -- USP1; Cancer -- Periodicals; Neoplasms -- Periodicals; Research -- Periodicals; Electronic journals; 616.994005
• DOI: 10.1111/cas.14375
• Languages: English
• ISSNs: 1347-9032

Abstract

Abstract: The histone demethylase lysine‐specific demethylase 4A (KDM4A) is reported to be overexpressed and plays a vital in multiple cancers through controlling gene expression by epigenetic regulation of H3K9 or H3K36 methylation marks. However, the biological role and mechanism of KDM4A in prostate cancer (PC) remain unclear. Herein, we reported KDM4A expression was upregulation in phosphatase and tensin homolog knockout mouse prostate tissue. Depletion of KDM4A in PC cells inhibited their proliferation and survival in vivo and vitro. Further studies reveal that USP1 is a deubiquitinase that regulates KDM4A K48‐linked deubiquitin and stability. Interestingly, we found c‐Myc was a key downstream effector of the USP1‐KDM4A/androgen receptor axis in driving PC cell proliferation. Notably, upregulation of KDM4A expression with high USP1 expression was observed in most prostate tumors and inhibition of USP1 promotes PC cells response to therapeutic agent enzalutamide. Our studies propose USP1 could be an anticancer therapeutic target in PC. Abstract : This study identifies USP1 as a critical deubiquitinase for stabilizing KDM4A, thereby promoting prostate cancer growth and tumorigenesis. Targeting KDM4A stabilization through pharmacological inhibition of USP1 by ML323 could thus open an avenue for therapeutic intervention in prostate cancer patients.