The KDM5 family of histone demethylases as targets in oncology drug discovery

Epigenomics. 2014 Jun;6(3):277-86. doi: 10.2217/epi.14.14.


There is growing evidence for a causal role of the KDM5 family of histone demethylases in human cancer. In particular, KDM5A (JARID1A/RBP2) and KDM5B (JARID1B/PLU1) contribute to cancer cell proliferation, reduce the expression of tumor suppressor genes, promote the development of drug tolerance and maintain tumor-initiating cells. KDM5 enzymes remove tri- and di-methylations of lysine 4 of histone H3 - modifications that occur at the start site of transcription in actively transcribed genes. However, the importance of the histone demethylase activity of KDM5 proteins for cancer cells has not been resolved so far. The currently available approaches suppress or remove the targeted proteins and thereby affect their putative functions as structural components and recruitment factors for other chromatin-associated proteins. Therefore, the development of specific enzymatic inhibitors for KDM5 will promote our understanding of the biological role of their catalytic activity and yield potential novel anticancer therapeutics.

Keywords: H3K4 methylation; cancer; enzymatic inhibitors; epigenetics; gene transcription; histone demethylase; jumonji; oncogenes.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Drug Design
  • Enzyme Inhibitors / pharmacology*
  • Gene Expression Regulation, Neoplastic
  • Histones / metabolism
  • Humans
  • Jumonji Domain-Containing Histone Demethylases / antagonists & inhibitors*
  • Jumonji Domain-Containing Histone Demethylases / metabolism
  • Neoplasms / metabolism
  • Neoplasms / pathology*
  • Nuclear Proteins / antagonists & inhibitors*
  • Nuclear Proteins / metabolism
  • Repressor Proteins / antagonists & inhibitors*
  • Repressor Proteins / metabolism
  • Retinoblastoma-Binding Protein 2 / antagonists & inhibitors*
  • Retinoblastoma-Binding Protein 2 / metabolism


  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Histones
  • Nuclear Proteins
  • Repressor Proteins
  • Jumonji Domain-Containing Histone Demethylases
  • KDM5A protein, human
  • KDM5B protein, human
  • Retinoblastoma-Binding Protein 2