KDM2B is involved in the epigenetic regulation of TGF-β-induced epithelial-mesenchymal transition in lung and pancreatic cancer cell lines

J Biol Chem. 2021 Jan-Jun;296:100213. doi: 10.1074/jbc.RA120.015502. Epub 2020 Dec 24.


Polycomb repressive complex-1 (PRC1) induces transcriptional repression by regulating monoubiquitination of lysine 119 of histone H2A (H2AK119) and as such is involved in a number of biological and pathological processes including cancer development. Previously we demonstrated that PRC2, which catalyzes the methylation of histone H3K27, has an essential function in TGF-β-induced epithelial-mesenchymal transition (EMT) of lung and pancreatic cancer cell lines. Since the cooperative activities of PRC1 and PRC2 are thought to be important for transcriptional repression in EMT program, we investigated the role of KDM2B, a member of PRC1 complex, on TGF-β-induced EMT in this study. Knockdown of KDM2B inhibited TGF-β-induced morphological conversion of the cells and enhanced cell migration and invasion potentials as well as the expression changes of EMT-related marker genes. Overexpression of KDM2B influenced the expression of several epithelial marker genes such as CDH1, miR200a, and CGN and enhanced the effects of TGF-β. Mechanistic investigations revealed that KDM2B specifically recognized the regulatory regions of CDH1, miR200a, and CGN genes and induced histone H2AK119 monoubiquitination as a component of PRC1 complex, thereby mediating the subsequent EZH2 recruitment and histone H3K27 methylation process required for gene repression. Studies using KDM2B mutants confirmed that its DNA recognition property but not its histone H3 demethylase activity was indispensable for its function during EMT. This study demonstrated the significance of the regulation of histone H2A ubiquitination in EMT process and provided the possibility to develop novel therapeutic strategies for the treatment of cancer metastasis.

Keywords: cancer biology; epithelial–mesenchymal transition; histone modification; polycomb repressive complex; transcription regulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, CD / metabolism
  • Cadherins / metabolism
  • Cell Line, Tumor
  • Enhancer of Zeste Homolog 2 Protein / metabolism
  • Epithelial-Mesenchymal Transition / drug effects*
  • F-Box Proteins / genetics
  • F-Box Proteins / metabolism*
  • Gene Expression Regulation, Neoplastic
  • Histones / genetics
  • Histones / metabolism*
  • Humans
  • Jumonji Domain-Containing Histone Demethylases / genetics
  • Jumonji Domain-Containing Histone Demethylases / metabolism*
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology*
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology*
  • Transforming Growth Factor beta / pharmacology*


  • Antigens, CD
  • CDH1 protein, human
  • Cadherins
  • F-Box Proteins
  • Histones
  • Transforming Growth Factor beta
  • Jumonji Domain-Containing Histone Demethylases
  • KDM2A protein, human
  • EZH2 protein, human
  • Enhancer of Zeste Homolog 2 Protein