SPOP mutation induces DNA methylation via stabilizing GLP/G9a

Nat Commun. 2021 Sep 29;12(1):5716. doi: 10.1038/s41467-021-25951-3.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Azacitidine / pharmacology
  • Azacitidine / therapeutic use
  • Cell Line, Tumor
  • DNA (Cytosine-5-)-Methyltransferases / antagonists & inhibitors
  • DNA (Cytosine-5-)-Methyltransferases / metabolism
  • DNA Methylation / drug effects
  • DNA Methylation / genetics*
  • Docetaxel / pharmacology
  • Docetaxel / therapeutic use
  • Down-Regulation / drug effects
  • Drug Resistance, Neoplasm / drug effects
  • Drug Resistance, Neoplasm / genetics
  • Drug Synergism
  • Epigenesis, Genetic / drug effects
  • Gene Expression Regulation, Neoplastic / drug effects
  • Genes, Tumor Suppressor
  • Histocompatibility Antigens / metabolism*
  • Histone-Lysine N-Methyltransferase / metabolism*
  • Humans
  • Male
  • Mice
  • Mutation
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Prostatic Neoplasms / drug therapy
  • Prostatic Neoplasms / genetics*
  • Prostatic Neoplasms / pathology
  • Protein Stability / drug effects
  • Proteolysis / drug effects
  • Repressor Proteins / genetics*
  • Repressor Proteins / metabolism
  • Xenograft Model Antitumor Assays


  • Histocompatibility Antigens
  • Nuclear Proteins
  • Repressor Proteins
  • SPOP protein, human
  • Docetaxel
  • EHMT1 protein, human
  • DNA (Cytosine-5-)-Methyltransferases
  • EHMT2 protein, human
  • Histone-Lysine N-Methyltransferase
  • Azacitidine