Targeting USP1-dependent KDM4A protein stability as a potential prostate cancer therapy

Cancer Sci. 2020 May;111(5):1567-1581. doi: 10.1111/cas.14375. Epub 2020 Mar 30.

Abstract

The histone demethylase lysine-specific demethylase 4A (KDM4A) is reported to be overexpressed and plays a vital in multiple cancers through controlling gene expression by epigenetic regulation of H3K9 or H3K36 methylation marks. However, the biological role and mechanism of KDM4A in prostate cancer (PC) remain unclear. Herein, we reported KDM4A expression was upregulation in phosphatase and tensin homolog knockout mouse prostate tissue. Depletion of KDM4A in PC cells inhibited their proliferation and survival in vivo and vitro. Further studies reveal that USP1 is a deubiquitinase that regulates KDM4A K48-linked deubiquitin and stability. Interestingly, we found c-Myc was a key downstream effector of the USP1-KDM4A/androgen receptor axis in driving PC cell proliferation. Notably, upregulation of KDM4A expression with high USP1 expression was observed in most prostate tumors and inhibition of USP1 promotes PC cells response to therapeutic agent enzalutamide. Our studies propose USP1 could be an anticancer therapeutic target in PC.

Keywords: KDM4A; USP1; deubiquitination; prostate cancer; tumorigenesis.

Publication types

  • Retracted Publication

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Benzamides
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Survival
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use*
  • Gene Expression
  • Gene Expression Regulation, Neoplastic / drug effects
  • HEK293 Cells
  • Humans
  • Jumonji Domain-Containing Histone Demethylases / genetics
  • Jumonji Domain-Containing Histone Demethylases / metabolism*
  • Male
  • Mice
  • Mice, Mutant Strains
  • Nitriles
  • PTEN Phosphohydrolase / deficiency
  • Phenylthiohydantoin / analogs & derivatives
  • Phenylthiohydantoin / pharmacology
  • Phenylthiohydantoin / therapeutic use
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology
  • Protein Binding / drug effects
  • Protein Stability / drug effects
  • Proto-Oncogene Proteins c-myc / genetics
  • Receptors, Androgen / genetics
  • Receptors, Androgen / metabolism
  • Signal Transduction / drug effects
  • Ubiquitin-Specific Proteases / antagonists & inhibitors*
  • Ubiquitin-Specific Proteases / genetics
  • Ubiquitin-Specific Proteases / metabolism
  • Ubiquitination / drug effects

Substances

  • AR protein, human
  • Antineoplastic Agents
  • Benzamides
  • Enzyme Inhibitors
  • MYC protein, human
  • Nitriles
  • Proto-Oncogene Proteins c-myc
  • Receptors, Androgen
  • Phenylthiohydantoin
  • enzalutamide
  • Jumonji Domain-Containing Histone Demethylases
  • KDM4A protein, human
  • PTEN Phosphohydrolase
  • Pten protein, mouse
  • USP1 protein, human
  • Ubiquitin-Specific Proteases