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.
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.
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.
KDM6A 是一种 X 染色体编码的组蛋白去甲基化酶，也是 COMPASS 样复合物的成员，在广泛的恶性肿瘤中经常发生突变，并通过特征不明的机制促进肿瘤发生。我们发现，KDM6A 的缺失通过 COMPASS 样复合物的失调和调节 ΔNp63、MYC 和 RUNX3 癌基因的超增强子的异常激活，选择性地诱导雌性的鳞状样、转移性胰腺癌。在男性中发展的这种肿瘤伴有 UTY 和 KDM6A 的同时缺失，表明存在重叠作用，并指向主要与去甲基化酶无关的肿瘤抑制功能。我们还证明，KDM6A 缺陷的胰腺癌对 BET 抑制剂具有选择性敏感性，该抑制剂逆转了鳞状分化并抑制了体内肿瘤生长，突出了为患者量身定制治疗方法的治疗靶点。
