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Prostate cancer-associated SPOP mutations lead to genomic instability through disruption of the SPOP-HIPK2 axis.
Jin, Xiaofeng; Qing, Shi; Li, Qian; Zhuang, Hui; Shen, Liliang; Li, Jinhui; Qi, Honggang; Lin, Ting; Lin, Zihan; Wang, Jian; Cao, Xinyi; Yang, Jianye; Ma, Qi; Cong, Linghua; Xi, Yang; Fang, Shuai; Meng, Xiaodan; Gong, Zhaohui; Ye, Meng; Wang, Shuyun; Wang, Chenji; Gao, Kun.
Affiliation
  • Jin X; The Affiliated Hospital of Medical School, Ningbo University, Ningbo 315020, China.
  • Qing S; Department of Biochemistry and Molecular Biology, Zhejiang Key Laboratory of Pathophysiology, Medical School of Ningbo University, Ningbo 315211, China.
  • Li Q; State Key Lab of Genetic Engineering, MOE Engineering Research Center of Gene Technology, School of Life Sciences, Fudan University, Shanghai 200438, China.
  • Zhuang H; The Affiliated Hospital of Medical School, Ningbo University, Ningbo 315020, China.
  • Shen L; Department of Biochemistry and Molecular Biology, Zhejiang Key Laboratory of Pathophysiology, Medical School of Ningbo University, Ningbo 315211, China.
  • Li J; The Affiliated Hospital of Medical School, Ningbo University, Ningbo 315020, China.
  • Qi H; Department of Biochemistry and Molecular Biology, Zhejiang Key Laboratory of Pathophysiology, Medical School of Ningbo University, Ningbo 315211, China.
  • Lin T; Department of Urology, Department of Hematology, the Affiliated Yinzhou Renmin Hospital of Medical School of Ningbo University, Ningbo 315040, China.
  • Lin Z; The Affiliated Hospital of Medical School, Ningbo University, Ningbo 315020, China.
  • Wang J; Department of Urology, the Affiliated Yinzhou Second Hospital of Medical School of Ningbo University, Ningbo 315100, China.
  • Cao X; The Affiliated Hospital of Medical School, Ningbo University, Ningbo 315020, China.
  • Yang J; Department of Biochemistry and Molecular Biology, Zhejiang Key Laboratory of Pathophysiology, Medical School of Ningbo University, Ningbo 315211, China.
  • Ma Q; The Affiliated Hospital of Medical School, Ningbo University, Ningbo 315020, China.
  • Cong L; Department of Biochemistry and Molecular Biology, Zhejiang Key Laboratory of Pathophysiology, Medical School of Ningbo University, Ningbo 315211, China.
  • Xi Y; The Affiliated Hospital of Medical School, Ningbo University, Ningbo 315020, China.
  • Fang S; Department of Biochemistry and Molecular Biology, Zhejiang Key Laboratory of Pathophysiology, Medical School of Ningbo University, Ningbo 315211, China.
  • Meng X; The Affiliated Hospital of Medical School, Ningbo University, Ningbo 315020, China.
  • Gong Z; Department of Biochemistry and Molecular Biology, Zhejiang Key Laboratory of Pathophysiology, Medical School of Ningbo University, Ningbo 315211, China.
  • Ye M; The Affiliated Hospital of Medical School, Ningbo University, Ningbo 315020, China.
  • Wang S; Department of Biochemistry and Molecular Biology, Zhejiang Key Laboratory of Pathophysiology, Medical School of Ningbo University, Ningbo 315211, China.
  • Wang C; Translational Research Laboratory for Urology, the Key Laboratory of Ningbo City. Ningbo First Hospital, The affiliated hospital of Ningbo University, Ningbo, Zhejiang 315010, China.
  • Gao K; Department of Urology, Department of Hematology, the Affiliated Yinzhou Renmin Hospital of Medical School of Ningbo University, Ningbo 315040, China.
Nucleic Acids Res ; 49(12): 6788-6803, 2021 07 09.
Article in En | MEDLINE | ID: mdl-34133717
ABSTRACT
Speckle-type Poz protein (SPOP), an E3 ubiquitin ligase adaptor, is the most frequently mutated gene in prostate cancer. The SPOP-mutated subtype of prostate cancer shows high genomic instability, but the underlying mechanisms causing this phenotype are still largely unknown. Here, we report that upon DNA damage, SPOP is phosphorylated at Ser119 by the ATM serine/threonine kinase, which potentiates the binding of SPOP to homeodomain-interacting protein kinase 2 (HIPK2), resulting in a nondegradative ubiquitination of HIPK2. This modification subsequently increases the phosphorylation activity of HIPK2 toward HP1γ, and then promotes the dissociation of HP1γ from trimethylated (Lys9) histone H3 (H3K9me3) to initiate DNA damage repair. Moreover, the effect of SPOP on the HIPK2-HP1γ axis is abrogated by prostate cancer-associated SPOP mutations. Our findings provide new insights into the molecular mechanism of SPOP mutations-driven genomic instability in prostate cancer.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Prostatic Neoplasms / Repressor Proteins / Nuclear Proteins / Carrier Proteins / Protein Serine-Threonine Kinases / Genomic Instability Type of study: Risk_factors_studies Limits: Humans / Male Language: En Journal: Nucleic Acids Res Year: 2021 Type: Article Affiliation country: China
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Prostatic Neoplasms / Repressor Proteins / Nuclear Proteins / Carrier Proteins / Protein Serine-Threonine Kinases / Genomic Instability Type of study: Risk_factors_studies Limits: Humans / Male Language: En Journal: Nucleic Acids Res Year: 2021 Type: Article Affiliation country: China