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In mice, losing the KDM6A gene turned pancreatic tumours squamous and metastatic, especially in females, by switching on growth regulators including MYC, and a drug class that blocks BET proteins reversed the change.
KDM6A, an X chromosome-encoded histone demethylase of the COMPASS-like complex, is frequently mutated across cancers. 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 delta-Np63, MYC and RUNX3. Tumours of this type in males had concomitant loss of UTY and KDM6A, pointing to demethylase-independent suppressor functions. KDM6A-deficient pancreatic cancer was selectively sensitive to BET inhibitors, which reversed squamous differentiation and restrained tumour growth in vivo.
It gives the 3 to 4% of KDM6A-mutant, squamous-programme tumours a mechanism and a candidate drug class.
Shares KDM6A, MYC, MYC, Pancreatic ductal adenocarcinoma.
Shares MYC, MYC, Pancreatic ductal adenocarcinoma.
Shares Epigenetic reprogramming, MYC.