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

Nat Genet. 2025 Jan;57(1):165-179. doi: 10.1038/s41588-024-02015-y.

Naitao Wang ^# ¹, Mohini R Pachai ^# ¹, Dan Li ^# ¹, Cindy J Lee ¹, Sarah Warda ¹, Makhzuna N Khudoynazarova ¹, Woo Hyun Cho ¹, Guojia Xie ², Sagar R Shah ³ ⁴, Li Yao ⁴ ⁵, Cheng Qian ¹, Elissa W P Wong ¹, Juan Yan ¹, Fanny V Tomas ¹, Wenhuo Hu ¹, Fengshen Kuo ⁶, Sizhi P Gao ¹, Jiaqian Luo ¹, Alison E Smith ¹, Ming Han ⁷, Dong Gao ⁷, Kai Ge ², Haiyuan Yu ⁴ ⁵, Sarat Chandarlapaty ¹ ⁸ ⁹, Gopakumar V Iyer ⁸ ⁹, Jonathan E Rosenberg ⁸ ⁹, David B Solit ¹ ⁸ ⁹, Hikmat A Al-Ahmadie ¹ ⁶, Ping Chi ¹⁰ ¹¹ ¹², Yu Chen ¹³ ¹⁴ ¹⁵

Affiliations

1 Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
2 National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
3 Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY, USA.
4 Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY, USA.
5 Department of Computational Biology, Cornell University, Ithaca, NY, USA.
6 Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
7 State Key Laboratory of Cell Biology, Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China.
8 Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
9 Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
10 Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. [email protected].
11 Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. [email protected].
12 Department of Medicine, Weill Cornell Medical College, New York, NY, USA. [email protected].
13 Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. [email protected].
14 Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. [email protected].
15 Department of Medicine, Weill Cornell Medical College, New York, NY, USA. [email protected].
# Contributed equally.

PMID: 39806204 DOI: 10.1038/s41588-024-02015-y

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.

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