A Novel Non-Cell Autonomous Tumor Suppressor Function of H3K27me3 Demethylase UTX/Kdm6a in Medulloblastoma

Ut Southwestern Medical Center, Dallas TX

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Abstract

Summary Immunotherapy is the most exciting development in recent years for cancer treatment. Tumor produced chemokines play important roles in attracting immune cells to tumor sites. In this proposal we aim to determine a non-cell autonomous tumor suppressor role of an epigenetic factor UTX/Kdm6a in activating tumor chemokine expression to attract T cell and inhibit tumor growth. The histone H3 lysine 27 (H3K27me3) demethylase UTX was recently identified as a potential tumor suppressor since mutations were found in various cancers including the pediatric brain tumor medulloblastoma (MB). UTX activates gene expression mainly by removing the repressive histone mark H3K27me3. However, the exact molecular functions of UTX in various cancers remain largely unclear. To understand the function of UTX in cancer, we deleted UTX in one of the well-characterized MB mouse model. Interestingly, UTX deletion led to significantly reduced survival and early tumor initiation, suggesting a tumor suppressor function of UTX. We compared the gene expression profiles in control and UTX-deficient MB tumors. Surprisingly, the most significantly changed genes are those involved in tumor induced host immune response including chemokine genes and immune genes. We hypothesize that UTX activates chemokine gene expression in MB that could induce host cytotoxic T cell recruitment to restrict tumor growth. We propose the following aims. (1). Evaluate the impaired host immune response to UTX-deficient MB. (2). Identify the UTX-regulated key chemokine genes necessary for T cell recruitment. Our discovery suggests an exciting possibility that an epigenetic regulator UTX may play a novel tumor suppressor function by inducing host immune response. The proposed studies will significantly further our understanding of UTX function in cancers and of how tumors trigger host immune protection, which may guide development of strategies for epigenetic- and chemokine-based cancer immunotherapies.