Loss of KMT2C or KMT2D primes urothelium for tumorigenesis and redistributes KMT2A-menin to bivalent promoters Journal Article
| Authors: | Wang, N.; Pachai, M. R.; Li, D.; Lee, C. J.; Warda, S.; Khudoynazarova, M. N.; Cho, W. H.; Xie, G.; Shah, S. R.; Yao, L.; Qian, C.; Wong, E. W. P.; Yan, J.; Tomas, F. V.; Hu, W.; Kuo, F.; Gao, S. P.; Luo, J.; Smith, A. E.; Han, M.; Gao, D.; Ge, K.; Yu, H.; Chandarlapaty, S.; Iyer, G. V.; Rosenberg, J. E.; Solit, D. B.; Al-Ahmadie, H. A.; Chi, P.; Chen, Y. |
| Article Title: | Loss of KMT2C or KMT2D primes urothelium for tumorigenesis and redistributes KMT2A-menin to bivalent promoters |
| 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. © 2025. The Author(s). |
| Keywords: | dna binding protein; promoter region; genetics; dna-binding proteins; mouse; animal; metabolism; animals; mice; mice, knockout; epidermal growth factor receptor; neoplasm proteins; cell differentiation; pathology; bladder tumor; urinary bladder neoplasms; carcinogenesis; cell transformation, neoplastic; gene expression regulation; urothelium; gene expression regulation, neoplastic; histone-lysine n-methyltransferase; promoter regions, genetic; tumor protein; knockout mouse; histone lysine methyltransferase; mixed lineage leukemia protein; myeloid-lymphoid leukemia protein; erbb receptors; humans; human; neoplastic cell transformation; kmt2d protein, human; kmt2a protein, mouse; kmt2c protein, human; kmt2d protein, mouse |
| Journal Title: | Nature Genetics |
| Volume: | 57 |
| ISSN: | 1061-4036 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2025-01-13 |
| Start Page: | 165 |
| End Page: | 179 |
| Language: | English |
| DOI: | 10.1038/s41588-024-02015-y |
| PUBMED: | 39806204 |
| PROVIDER: | scopus |
| PMCID: | PMC11735410 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- MSK corresponding authors are Ping Chi and Yu Chen -- Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
MSK Authors
Related MSK Work