KMT2D Loss Promotes Head and Neck Squamous Carcinoma Through Enhancer Reprogramming and Modulation of Immune Microenvironment
KMT2D Loss Promotes Head and Neck Squamous Carcinoma Through Enhancer Reprogramming and Modulation of Immune Microenvironment
ABSTRACT Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, with 5-year survival of ～50%. Genomic profiling studies have identified important somatic mutations in this disease which presents an opportunity for precision medicine. We demonstrate that KMT2D, a histone methyltransferase harbors somatic mutations in ～17% of HNSCC and is associated with 2-year recurrence in TCGA data. Consistent with algorithmic prediction of bring a driver tumor-suppressor event, its loss results in larger oral tumors in immune-proficient orthotopic models. Mechanistically, we find that KMT2D knockdown or KMT2D mutation causes loss of H3K4me1-marked enhancers harboring IRF7/9 binding sites, which is known to regulate interferon signaling. Indeed, KMT2D loss in human and murine cell lines deregulated transcriptional levels of cytokine expression and impacted numerous immune signaling pathways, including interferon signaling. Consistently, Kmt2d knockdown in murine tumors exhibited decrease in IFNγ-producing effector T cells and an increase in T-cells with an exhausted phenotype. Epistasis experiments showed that exogenous treatment with IFNγ abrogated the increased tumor growth in Kmt2d-deficient oral tumors. Together, these results support the role of KMT2D as a tumor suppressor in HNSCC that regulates the tumor microenvironment by modulating H3K4me1-marked enhancers controlling interferon signaling.
Singh Anand K、Arslan Emre、Liu Zhiyi、Anvar Nazanin、Xie Tongxin、Schulz Jonathan、Amit Moran、Tang Ming、Myers Jeffrey N、Barrodia Praveen、Callahan S. Carson、Rai Kunal、Yang Jiah、Jiang Shan、Divenko Margarita
Department of Genomic Medicine, The University of Texas MD Anderson Cancer CenterDepartment of Genomic Medicine, The University of Texas MD Anderson Cancer CenterDepartment of Genomic Medicine, The University of Texas MD Anderson Cancer Center||Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer CenterDepartment of Genomic Medicine, The University of Texas MD Anderson Cancer Center||MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, University of Texas MD Anderson Cancer CenterDepartment of Head and Neck Surgery, The University of Texas MD Anderson Cancer CenterDepartment of Genomic Medicine, The University of Texas MD Anderson Cancer Center||MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, University of Texas MD Anderson Cancer CenterDepartment of Head and Neck Surgery, The University of Texas MD Anderson Cancer CenterDepartment of Genomic Medicine, The University of Texas MD Anderson Cancer Center||FAS informatics Group, Harvard University||Department of Molecular and Cellular Biology, Center for Brain Science, Harvard University and Howard Hughes Medical InstituteDepartment of Head and Neck Surgery, The University of Texas MD Anderson Cancer CenterDepartment of Genomic Medicine, The University of Texas MD Anderson Cancer CenterDepartment of Genomic Medicine, The University of Texas MD Anderson Cancer Center||Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center||MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, University of Texas MD Anderson Cancer CenterDepartment of Genomic Medicine, The University of Texas MD Anderson Cancer CenterDepartment of Genomic Medicine, The University of Texas MD Anderson Cancer Center||MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, University of Texas MD Anderson Cancer CenterDepartment of Genomic Medicine, The University of Texas MD Anderson Cancer CenterDepartment of Genomic Medicine, The University of Texas MD Anderson Cancer Center
肿瘤学基础医学口腔科学
Singh Anand K,Arslan Emre,Liu Zhiyi,Anvar Nazanin,Xie Tongxin,Schulz Jonathan,Amit Moran,Tang Ming,Myers Jeffrey N,Barrodia Praveen,Callahan S. Carson,Rai Kunal,Yang Jiah,Jiang Shan,Divenko Margarita.KMT2D Loss Promotes Head and Neck Squamous Carcinoma Through Enhancer Reprogramming and Modulation of Immune Microenvironment[EB/OL].(2025-03-28)[2025-05-05].https://www.biorxiv.org/content/10.1101/2021.09.21.461314.点此复制
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