SPOP mutation induces DNA methylation via stabilizing GLP/G9a

Jianong Zhang, Kun Gao, Hongyan Xie, Dejie Wang, Pingzhao Zhang, Ting Wei, Yuqian Yan, Yunqian Pan, Wenbin Ye, Huifen Chen, Qing Shi, Yao Li, Shi-min Zhao, Xiaonan Hou, Saravut J. Weroha, Yuzhuo Wang, Jun Zhang, R. Jeffrey Karnes, Housheng Hansen He, Liguo Wang, Chenji Wang () and Haojie Huang ()
Additional contact information
Jianong Zhang: Fudan University
Kun Gao: School of Medicine, Tongji University
Hongyan Xie: Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science
Dejie Wang: Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science
Pingzhao Zhang: Fudan University
Ting Wei: Divison of Computational Biology, Mayo Clinic College of Medicine and Science
Yuqian Yan: Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science
Yunqian Pan: Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science
Wenbin Ye: Xiamen University
Huifen Chen: School of Medicine, Tongji University
Qing Shi: Fudan University
Yao Li: Fudan University
Shi-min Zhao: Fudan University
Xiaonan Hou: Department of Oncology, Mayo Clinic College of Medicine
Saravut J. Weroha: Department of Oncology, Mayo Clinic College of Medicine
Yuzhuo Wang: Department of Experimental Therapeutics, BC Cancer Research Centre
Jun Zhang: Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine and Science
R. Jeffrey Karnes: Department of Urology, Mayo Clinic College of Medicine and Science
Housheng Hansen He: University of Toronto
Liguo Wang: Divison of Computational Biology, Mayo Clinic College of Medicine and Science
Chenji Wang: Fudan University
Haojie Huang: Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: Abstract Mutations in SPOP E3 ligase gene are reportedly associated with genome-wide DNA hypermethylation in prostate cancer (PCa) although the underlying mechanisms remain elusive. Here, we demonstrate that SPOP binds and promotes polyubiquitination and degradation of histone methyltransferase and DNMT interactor GLP. SPOP mutation induces stabilization of GLP and its partner protein G9a and aberrant upregulation of global DNA hypermethylation in cultured PCa cells and primary PCa specimens. Genome-wide DNA methylome analysis shows that a subset of tumor suppressor genes (TSGs) including FOXO3, GATA5, and NDRG1, are hypermethylated and downregulated in SPOP-mutated PCa cells. DNA methylation inhibitor 5-azacytidine effectively reverses expression of the TSGs examined, inhibits SPOP-mutated PCa cell growth in vitro and in mice, and enhances docetaxel anti-cancer efficacy. Our findings reveal the GLP/G9a-DNMT module as a mediator of DNA hypermethylation in SPOP-mutated PCa. They suggest that SPOP mutation could be a biomarker for effective treatment of PCa with DNA methylation inhibitor alone or in combination with taxane chemotherapeutics.

Date: 2021
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DOI: 10.1038/s41467-021-25951-3

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