Acetylated KHSRP impairs DNA‐damage‐response‐related mRNA decay and facilitates prostate cancer tumorigenesis

• Published in: Molecular oncology Vol. 18; no. 9; pp. 2314 - 2330
• Main Authors: Yuan, Haihua, Cai, Renjie, Chen, Biying, Wang, Qian, Wang, Mengting, An, Junyi, An, Weishu, Tao, Ye, Yu, Jianxiu, Jiang, Bin, Zhang, Yanjie, Xu, Ming
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.09.2024; John Wiley and Sons Inc; Wiley
• Subjects: 3' Untranslated regions; Acetylation; Acetylation - drug effects; Androgens; Animals; Antibodies; Breast cancer; Carcinogenesis - genetics; Carcinogenesis - pathology; Castration; Cell growth; Cell Line, Tumor; DNA Damage; DNA damage response; Enzymes; Fractionation; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Gene set enrichment analysis; Genes; Homology; Humans; KHSRP; Kinases; Laboratory animals; Male; Mice; Mice, Nude; MicroRNAs; mRNA turnover; Mutagenesis; Phosphorylation; Post‐translational Modification; Prostate Cancer; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Proteins; Ribonucleoprotein K; RNA Stability - genetics; RNA-binding protein; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; Sirtuins - genetics; Sirtuins - metabolism; Trans-Activators; Tumorigenesis; United States > US; China; prostate cancer; Acetylation; tumorigenesis; DNA damage response; KHSRP
• ISSN: 1574-7891; 1878-0261; 1878-0261
• DOI: 10.1002/1878-0261.13634

Androgen‐regulated DNA damage response (DDR) is one of the essential mechanisms in prostate cancer (PCa), a hormone‐sensitive disease. The heterogeneous nuclear ribonucleoprotein K (hnRNPK)‐homology splicing regulatory protein known as far upstream element‐binding protein 2 (KHSRP) is an RNA‐binding protein that can attach to AU‐rich elements in the 3′ untranslated region (3′‐UTR) of messenger RNAs (mRNAs) to mediate mRNA decay and emerges as a critical regulator in the DDR to preserve genome integrity. Nevertheless, how KHSRP responds to androgen‐regulated DDR in PCa development remains unclear. This study found that androgen can significantly induce acetylation of KHSRP, which intrinsically drives tumor growth in xenografted mice. Moreover, enhanced KHSRP acetylation upon androgen stimuli impedes KHSRP‐regulated DDR gene expression, as seen by analyzing RNA sequencing (RNA‐seq) and Gene Set Enrichment Analysis (GSEA) datasets. Additionally, NAD‐dependent protein deacetylase sirtuin‐7 (SIRT7) is a promising deacetylase of KHSRP, and androgen stimuli impairs its interaction with KHSRP to sustain the increased KHSRP acetylation level in PCa. We first report the acetylation of KHSRP induced by androgen, which interrupts the KHSRP‐regulated mRNA decay of the DDR‐related genes to promote the tumorigenesis of PCa. This study provides insight into KHSRP biology and potential therapeutic strategies for PCa treatment, particularly that of castration‐resistant PCa. KHSRP deacetylated by SIRT7 feasibly decays mRNAs of DNA damage response (DDR) genes to weaken DNA repair ability, resulting in prostate cancer (PCa) cell death. KHSRP–SIRT7 interaction is attenuated upon androgen receptor (AR) activation in PCa cells, which leads to acetylated KHSRP inefficiently reaching the adenine uridine (AU)‐rich elements (AREs) in the 3′‐UTR of DDR genes to exert mRNA decay function.