KDM6A regulates immune response genes in multiple myeloma
Daphne Dupéré-Richer, Alberto Riva, Benjamin G. Barwick, Sayantan Maji, Heidi Casellas Román, Jianping Li, Umasankar De, Amin Sobh, Gabrielle Quickstad, Crissandra Piper, Marta Kulis, Teresa Ezponda, José I. Martín‐Subero, Giovanni Tonon, Weizhou Zhang, Constantine S. Mitsiades, Lawrence Boise, Richard L. Bennett, Jonathan D. Licht
Abstract
ABSTRACT: The histone H3 at lysine 27 (H3K27) demethylase lysine demethylase 6A (KDM6A) is a tumor suppressor in multiple cancers, including multiple myeloma (MM). We created isogenic MM cells disrupted for KDM6A and tagged the endogenous protein to facilitate genome-wide studies. KDM6A binds genes associated with immune recognition and cytokine signaling. Most importantly, KDM6A binds and activates NLRC5 and CIITA, which encode regulators of major histocompatibility complex genes. Patient data indicate that NLRC5 and CIITA are downregulated in MM with low KDM6A expression. Chromatin analysis shows that KDM6A binds poised and active enhancers and KDM6A loss led to decreased H3K27ac at enhancers, increased H3K27me3 levels in body of genes bound by KDM6A, and decreased gene expression. Reestablishing histone acetylation with an HDAC3 inhibitor leads to upregulation of major histocompatibility complex expression, offering a strategy to restore immunogenicity of KDM6A-deficient tumors. Loss of Kdm6a in Kirsten rat sarcoma virus (K-RAS)-transformed murine fibroblasts led to increased growth in vivo associated with decreased T-cell infiltration.