Loss of KDM6A Activates Super-Enhancers to Induce Gender-Specific Squamous-like Pancreatic Cancer and Confers Sensitivity to BET Inhibitors

Cancer Cell. 2018 Mar 12;33(3):512-526.e8. doi: 10.1016/j.ccell.2018.02.003.


KDM6A, an X chromosome-encoded histone demethylase and member of the COMPASS-like complex, is frequently mutated in a broad spectrum of malignancies and contributes to oncogenesis with poorly characterized mechanisms. We found that KDM6A loss induced squamous-like, metastatic pancreatic cancer selectively in females through deregulation of the COMPASS-like complex and aberrant activation of super-enhancers regulating ΔNp63, MYC, and RUNX3 oncogenes. This subtype of tumor developed in males had concomitant loss of UTY and KDM6A, suggesting overlapping roles, and points to largely demethylase independent tumor suppressor functions. We also demonstrate that KDM6A-deficient pancreatic cancer is selectively sensitive to BET inhibitors, which reversed squamous differentiation and restrained tumor growth in vivo, highlighting a therapeutic niche for patient tailored therapies.

Keywords: COMPASS-like complex; JQ1; KDM6A; KMT2D; MYC; UTY; p63; pancreatic cancer; squamous; super-enhancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Squamous Cell
  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • Gene Expression Regulation, Neoplastic / genetics*
  • Histone Demethylases / deficiency*
  • Histone Demethylases / genetics
  • Humans
  • Mice
  • Mutation / genetics*
  • Nuclear Proteins / deficiency*
  • Pancreatic Neoplasms / genetics*
  • Xenograft Model Antitumor Assays / methods


  • Nuclear Proteins
  • Histone Demethylases
  • KDM6A protein, human
  • Utx protein, mouse