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 WangChenji Wang, Haojie Huang

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Article number5716
JournalNature communications
Issue number1
StatePublished - Dec 1 2021

ASJC Scopus subject areas

  • Physics and Astronomy(all)
  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)


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