美国纪念斯隆-凯特琳癌症中心Yu Chen等研究人员合作发现，Kmt2c或Kmt2d的缺失使尿路上皮易于发生肿瘤，并将KMT2A–menin重新分布至双效启动子。相关论文于2025年1月13日在线发表在《自然—遗传学》杂志上。

研究人员通过基因工程小鼠模型证明，尿路上皮中敲除Kmt2c/d会导致分化受损、对生长和炎症刺激的反应增强，并使其对致癌物和致癌基因的致癌转化更加敏感。在机制上，KMT2D定位于活性增强子和富含CpG的启动子，这些区域优先调控尿路上皮谱系程序。Kmt2c/d的敲除导致这些位点的H3K4me1、H3K27ac和新生RNA转录水平下降，从而引发分化障碍。

此外，Kmt2c/d的敲除还导致KMT2A–menin从KMT2D定位的增强子，重新分布至富含CpG和双效启动子，进而解除信号诱导的即刻早期基因的抑制。治疗方面，Kmt2c/d的敲除上调了表皮生长因子受体信号传导，并使其对表皮生长因子受体抑制剂表现出敏感性。

综上所述，这些数据表明，Kmt2c/d的功能丧失引发了一种分子“场效应”，使组织学上正常的尿路上皮易于发生致癌转化，并揭示了潜在的治疗脆弱性。

研究人员表示，KMT2C/D–KDM6A复合体的成员在尿路上皮癌，和组织学上正常的尿路上皮中反复发生突变。

附：英文原文

Title: Loss of Kmt2c or Kmt2d primes urothelium for tumorigenesis and redistributes KMT2A–menin to bivalent promoters

Author: Wang, Naitao, Pachai, Mohini R., Li, Dan, Lee, Cindy J., Warda, Sarah, Khudoynazarova, Makhzuna N., Cho, Woo Hyun, Xie, Guojia, Shah, Sagar R., Yao, Li, Qian, Cheng, Wong, Elissa W. P., Yan, Juan, Tomas, Fanny V., Hu, Wenhuo, Kuo, Fengshen, Gao, Sizhi P., Luo, Jiaqian, Smith, Alison E., Han, Ming, Gao, Dong, Ge, Kai, Yu, Haiyuan, Chandarlapaty, Sarat, Iyer, Gopakumar V., Rosenberg, Jonathan E., Solit, David B., Al-Ahmadie, Hikmat A., Chi, Ping, Chen, Yu

Issue&Volume: 2025-01-13

Abstract: Members of the KMT2C/D–KDM6A complex are recurrently mutated in urothelial carcinoma and in histologically normal urothelium. Here, using genetically engineered mouse models, we demonstrate that Kmt2c/d knockout in the urothelium led to impaired differentiation, augmented responses to growth and inflammatory stimuli and sensitization to oncogenic transformation by carcinogen and oncogenes. Mechanistically, KMT2D localized to active enhancers and CpG-poor promoters that preferentially regulate the urothelial lineage program and Kmt2c/d knockout led to diminished H3K4me1, H3K27ac and nascent RNA transcription at these sites, which leads to impaired differentiation. Kmt2c/d knockout further led to KMT2A–menin redistribution from KMT2D localized enhancers to CpG-high and bivalent promoters, resulting in derepression of signal-induced immediate early genes. Therapeutically, Kmt2c/d knockout upregulated epidermal growth factor receptor signaling and conferred vulnerability to epidermal growth factor receptor inhibitors. Together, our data posit that functional loss of Kmt2c/d licenses a molecular ‘field effect’ priming histologically normal urothelium for oncogenic transformation and presents therapeutic vulnerabilities.

DOI: 10.1038/s41588-024-02015-y

Source: https://www.nature.com/articles/s41588-024-02015-y