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

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

Author information

1
Cancer Epigenetics Laboratory, Department of Anatomy and Regenerative Biology, George Washington University (GWU) School of Medicine and Health Sciences, Washington, DC 20052, USA; GWU Cancer Center, GWU School of Medicine and Health Sciences, Washington, DC 20052, USA.
2
Cancer Epigenetics Laboratory, Department of Anatomy and Regenerative Biology, George Washington University (GWU) School of Medicine and Health Sciences, Washington, DC 20052, USA; GWU Cancer Center, GWU School of Medicine and Health Sciences, Washington, DC 20052, USA; Department of Physics, GWU, Washington, DC 20052, USA.
3
Cancer Epigenetics Laboratory, Department of Anatomy and Regenerative Biology, George Washington University (GWU) School of Medicine and Health Sciences, Washington, DC 20052, USA.
4
GWU Cancer Center, GWU School of Medicine and Health Sciences, Washington, DC 20052, USA; Department of Physics, GWU, Washington, DC 20052, USA.
5
Cancer Epigenetics Laboratory, Department of Anatomy and Regenerative Biology, George Washington University (GWU) School of Medicine and Health Sciences, Washington, DC 20052, USA; GWU Cancer Center, GWU School of Medicine and Health Sciences, Washington, DC 20052, USA. Electronic address: atzatsos@gwu.edu.

Abstract

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

PMID:
29533787
PMCID:
PMC5854186
[Available on 2019-03-12]
DOI:
10.1016/j.ccell.2018.02.003

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