KDM6A Loss Induces Aggressive Pancreatic Cancer in Mice

KDM6A is an X chromosome–encoded histone demethylase and a component of the COMPASS-like complex, which monomethylates H3K4 to delimit enhancer chromatin. It is frequently mutated in a variety of tumor types including pancreatic cancer and its loss of function has been linked to tumorigenesis. However, the mechanisms by which KDM6A loss promotes pancreatic cancer remain poorly understood. Andricovich and colleagues found that mutations and deletions in KDM6A occurred frequently in squamous-like and metastatic pancreatic cancer. In mice with Kras^G12D-driven PanIN lesions, which rarely progress to invasive pancreatic cancer, loss of Kdm6a induced aggressive, metastatic squamous-like pancreatic tumors in female mice, whereas male mice developed well differentiated pancreatic ductal adenocarcinoma. In male mice, concomitant loss of the Y chromosome-encoded KDM6 family member UTY, which lacks demethylase activity, resulted in a similar phenotype to Kdm6a loss alone in female mice. Kdm6a loss resulted in gene expression changes independent of H3K27me3 that promoted squamous and quasi-mesenchymal differentiation in female mice. Mechanistically, loss of KDM6A deregulated the COMPASS-like complex, disrupting the superenhancer landscape to promote aberrant activation oncogenes including ΔNp63, MYC, and RUNX3, suggesting the potential for epigenetic inhibitor therapies. A small-molecule screen in 17 human pancreatic cancer cell lines revealed that KDM6A-deficient cells are sensitive to bromodomain and extraterminal domain (BET) inhibitors including JQ1, iBET151, and bromosporine. JQ1 treatment reduced BRD4 occupancy at the superenhancers driving ΔNp63, MYC, and RUNX3 expression. In vivo, JQ1 treatment inhibited squamous differentiation and suppressed the growth of Kdm6a-deficient pancreatic tumors. The identification of KDM6A loss as a gender-specific driver of oncogenic superenhancer activation in pancreatic cancer suggests the potential for BET inhibitors for the treatment of patients with KDM6A-deficient tumors.

Andricovich J, Perkail S, Kai Y, Casasanta N, Peng W, Tzatsos A. Loss of KDM6A activates super-enhancers to induce gender-specific squamous-like pancreatic cancer and confers sensitivity to BET inhibitors. Cancer Cell 2018;33:512–26.e8.

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