Histone demethylase UTX/KDM6A enhances tumor immune cell recruitment, promotes differentiation and suppresses medulloblastoma

• Published in: Cancer letters Vol. 499; pp. 188 - 200
• Main Authors: Yi, Jiaqing, Shi, Xuanming, Xuan, Zhenyu, Wu, Jiang
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 28.02.2021; Elsevier Limited
• Subjects: Animal models; Animals; Basic Helix-Loop-Helix Transcription Factors - genetics; Brain cancer; Brain tumors; Cancer immunotherapy; Cancer therapies; CD8 antigen; Cell adhesion & migration; Cell differentiation; Cell Differentiation - genetics; Cell Line, Tumor; Cell migration; Cell proliferation; Cerebellar Neoplasms - genetics; Cerebellar Neoplasms - immunology; Cerebellar Neoplasms - pathology; Cerebellum; Cerebellum - cytology; Cerebellum - pathology; Chemokines; Children; Chromosomes; Cloning; Cytotoxicity; Disease Models, Animal; Epigenetics; Female; Flow cytometry; Gene expression; Gene Expression Regulation, Neoplastic - immunology; Gene Knockdown Techniques; Genetic engineering; Histone Demethylases - genetics; Histone Demethylases - metabolism; Histones; Humans; Immunotherapy; Infections; Jumonji Domain-Containing Histone Demethylases - genetics; Jumonji Domain-Containing Histone Demethylases - metabolism; Lymphocytes; Lymphocytes T; Lymphocytes, Tumor-Infiltrating - immunology; Male; Medulloblastoma; Medulloblastoma - genetics; Medulloblastoma - immunology; Medulloblastoma - pathology; Mice; Mice, Transgenic; Mutation; Neoplastic Stem Cells - pathology; Neural stem cells; Neuronal differentiation; Neurons - pathology; Neuropeptides - genetics; Primary Cell Culture; Proteins; SHH medulloblastoma; Smoothened Receptor - genetics; T cell migration; T-Lymphocytes, Cytotoxic - immunology; Th1-type chemokines; Tumor Microenvironment - genetics; Tumor Microenvironment - immunology; Tumor suppressor genes; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Tumorigenesis; Tumors; UTX/KDM6A; United States > US; Texas; Neuronal differentiation; UTX/KDM6A; Th1-type chemokines; T cell migration; SHH medulloblastoma
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2020.11.031

The deregulation of epigenetic pathways has been implicated as a critical step in tumorigenesis including in childhood brain tumor medulloblastoma. The H3K27me3 demethylase UTX/KDM6A plays important roles in development and is frequently mutated in various types of cancer. However, how UTX regulates tumor development remains largely unclear. Here, we report the generation of a UTX-deleted mouse model of SHH medulloblastoma that demonstrates the tumor suppressor functions of UTX, which could be antagonized by the deletion of another H3K27me3 demethylase JMJD3/KDM6B. Intriguingly, UTX deletion in cancerous cerebellar granule neuron precursors (CGNPs) resulted in the impaired recruitment of host CD8+ T cells to the tumor microenvironment through a non-cell autonomous mechanism. In both mouse medulloblastoma models and in human medulloblastoma cells, we showed that UTX activates Th1-type chemokines, which are responsible for T cell migration. Surprisingly, our results showed that the depletion of cytotoxic CD8+ T cells did not affect mouse medulloblastoma growth. Nevertheless, the UTX/chemokine/T cell recruitment pathway we identified may be applied to many other cancers and may be important for improving cancer immunotherapy. In addition, UTX is required for the expression of NeuroD2 in precancerous progenitors, which encodes a potent proneural transcription factor. Overexpression of NEUROD2 in CGNPs decreased cell proliferation and increased neuron differentiation. We showed that UTX deletion led to impaired neural differentiation, which could coordinate with active SHH signaling to accelerate medulloblastoma development. Thus, UTX regulates both cell-intrinsic oncogenic processes and the tumor microenvironment in medulloblastoma. Our study provides insights into both medulloblastoma development and context dependent functions of UTX in tumorigenesis. •UTX functions as a tumor suppressor in SHH-subgroup medulloblastoma.•UTX and JMJD3 play opposite roles in medulloblastoma tumorigenesis.•UTX activates Th-1 type chemokine expression, and enhances T cell recruitment.•UTX activates NeuroD2 expression and neuronal differentiation.