Loss of KDM6A Activates Super-Enhancers to Induce Gender-Specific Squamous-like Pancreatic Cancer and Confers Sensitivity to BET Inhibitors.
Loss of KDM6A Activates Super-Enhancers to Induce Gender-Specific Squamous-like Pancreatic Cancer and Confers Sensitivity to BET Inhibitors.
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DOI：
10.1016/j.ccell.2018.02.003
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发表时间：
2018-03-12
期刊：
影响因子：
50.3
通讯作者：
Tzatsos A
中科院分区：
文献类型：
--
作者：
Andricovich J;Perkail S;Kai Y;Casasanta N;Peng W;Tzatsos A
KDM6A是一种编码组蛋白去甲基化酶的X染色体，也是compass样复合体的成员，在广泛的恶性肿瘤中经常发生突变，并导致肿瘤发生，但机制尚不明确。我们发现KDM6A缺失通过解除compass样复合体和异常激活调节ΔNp63、MYC和RUNX3癌基因的超增强子，选择性地诱导了女性鳞状样转移性胰腺癌。在男性中发生的这种肿瘤亚型伴随着UTY和KDM6A的缺失，这表明它们的作用是重叠的，并且在很大程度上指向去甲基化酶独立的肿瘤抑制功能。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，BET抑制剂在体内逆转鳞状分化并抑制肿瘤生长，这突出了患者定制治疗的治疗利基。
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.
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影响因子：
64.5
作者：
Basu A;Bodycombe NE;Cheah JH;Price EV;Liu K;Schaefer GI;Ebright RY;Stewart ML;Ito D;Wang S;Bracha AL;Liefeld T;Wawer M;Gilbert JC;Wilson AJ;Stransky N;Kryukov GV;Dancik V;Barretina J;Garraway LA;Hon CS;Munoz B;Bittker JA;Stockwell BR;Khabele D;Stern AM;Clemons PA;Shamji AF;Schreiber SL
通讯作者：
Schreiber SL
选择性抑制BET溴结构域。
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
64.5
作者：
Hnisz D;Abraham BJ;Lee TI;Lau A;Saint-André V;Sigova AA;Hoke HA;Young RA
通讯作者：
Young RA
DOI：
10.1073/pnas.0707292104
发表时间：
2007-11-20
影响因子：
11.1
作者：
Hong, SunHwa;Cho, Young-Wook;Ge, Kai
通讯作者：
Ge, Kai
影响因子：
64.8
作者：
Agger, Karl;Cloos, Paul A. C.;Helin, Kristian
通讯作者：
Helin, Kristian