Loss of KDM6A Activates Super-Enhancers to Induce Gender-Specific Squamous-like Pancreatic Cancer and Confers Sensitivity to BET Inhibitors

被引：238

作者：

Andricovich, Jaclyn ^{[1
,2
]}

Perkail, Stephanie ^{[1
,2
]}

Kai, Yan ^{[1
,2
,3
]}

Casasanta, Nicole ^{[1
]}

Peng, Weiqun ^{[2
,3
]}

Tzatsos, Alexandros ^{[1
,2
]}

机构：

[1] GWU, Dept Anat & Regenerat Biol, Canc Epigenet Lab, Sch Med & Hlth Sci, Washington, DC 20052 USA

[2] GWU Canc Ctr, GWU Sch Med & Hlth Sci, Washington, DC 20052 USA

[3] GWU, Dept Phys, Washington, DC 20052 USA

来源：

CANCER CELL | 2018年 / 33卷 / 03期

关键词：

DUCTAL ADENOCARCINOMA; CELL IDENTITY; DEMETHYLASE; GENE; UTX; IDENTIFICATION; CHROMATIN; DIFFERENTIATION; IMMORTALIZATION; HETEROGENEITY;

D O I：

10.1016/j.ccell.2018.02.003

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 Delta Np63, 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.

引用

页码：512 / +

页数：23

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