biostudies-literatureZhang HZhejiang Engineering Research Center of Innovative technologies and diagnostic and therapeutic equipment for urinary system diseasesThe National Natural Science Foundation of ZhejiangThe K.C. Wong Magna Fund in Ningbo UniversityThe Ningbo Top Medical and Health Research ProgramThe Youth Science and Technology Innovation Leader of NingboThe National Natural Science Foundation of ChinaThe Ningbo Clinical Research Center for Urological Diseasee186871https://www.ebi.ac.uk/biostudies/studies/S-EPMC12016936biostudies-literatureUnknown10(8)It is well documented that impaired DNA damage repair (DDR) induces genomic instability that can efficiently increase the sensitivity of prostate cancer (PCa) cells to PARP inhibitors; however, the underlying mechanism remains elusive. Here, we found profound genomic instability in PCa cells with SPOP gene mutations and confirmed the sensitivity of SPOP-mutated PCa cells to olaparib-induced apoptosis. Mechanistically, we identified olaparib-induced CK2-mediated phosphorylation of PIAS1-S468, which in turn mediated SUMOylation of SPOP, thus promoting its E3 ligase activity in the DDR. Moreover, an abnormal CK2/PIAS1/SPOP axis due to SPOP mutations or defects in CK2-mediated phosphorylation of PIAS1, as well as SPOP inhibitor treatment, led to impaired DDR, thus increasing olaparib-induced aJCI insightSPOP mutations increase PARP inhibitor sensitivity via CK2/PIAS1/SPOP axis in prostate cancer.PMC1201693632270821LTGY24H160005LY24C05000120220202032019A21001Not Applicable2023QL052Zheng ZKong LChai LLi JWu LJin XLv XZhang HZhao YLiu YLiu ZYan ZCao XYou HJin JfalseSPOP mutations increase PARP inhibitor sensitivity via CK2/PIAS1/SPOP axis in prostate cancer.It is well documented that impaired DNA damage repair (DDR) induces genomic instability that can efficiently increase the sensitivity of prostate cancer (PCa) cells to PARP inhibitors; however, the underlying mechanism remains elusive. Here, we found profound genomic instability in PCa cells with SPOP gene mutations and confirmed the sensitivity of SPOP-mutated PCa cells to olaparib-induced apoptosis. Mechanistically, we identified olaparib-induced CK2-mediated phosphorylation of PIAS1-S468, which in turn mediated SUMOylation of SPOP, thus promoting its E3 ligase activity in the DDR. Moreover, an abnormal CK2/PIAS1/SPOP axis due to SPOP mutations or defects in CK2-mediated phosphorylation of PIAS1, as well as SPOP inhibitor treatment, led to impaired DDR, thus increasing olaparib-induced a2025-01-01T00:00:00Z2025 Apr2026-06-01T12:53:32.873Z2025-07-10T03:09:06.858ZS-EPMC120169364026091510.1172/jci.insight.186871