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.

中文翻译：

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KDM6A的丢失会激活超级增强剂，从而诱导特定性别的鳞状胰腺癌，并使BET抑制剂具有敏感性。

KDM6A是X染色体编码的组蛋白脱甲基酶，是COMPASS样复合物的成员，经常在广泛的恶性肿瘤中发生突变，并以机制较差的机制促成肿瘤发生。我们发现，KDM6A缺失可通过解除COMPASS样复合物的调节以及调节ΔNp63，MYC和RUNX3癌基因的超级增强剂的异常激活，选择性地诱导女性鳞状样转移性胰腺癌。这种在男性中发展成的肿瘤亚型伴随着UTY和KDM6A的丧失，提示作用重叠，并且指出了很大程度上与脱甲基酶无关的肿瘤抑制功能。我们还证明，KDM6A缺陷型胰腺癌对BET抑制剂具有选择性敏感性，而BET抑制剂可逆转鳞状细胞分化并抑制体内肿瘤的生长，