Division of Hematology/Oncology, University of Florida Health Cancer Center, University of Florida, Gainesville, FL.
Interdisciplinary Center for Biotechnology Research, University of Florida, Gainesville, FL.
Blood. 2024 Oct 3;144(14):1508-1520. doi: 10.1182/blood.2024024518.
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.
组蛋白 H3 赖氨酸 27 去甲基化酶赖氨酸去甲基化酶 6A（KDM6A）是多种癌症（包括多发性骨髓瘤 [MM]）中的肿瘤抑制因子。我们构建了 KDM6A 缺失的同基因 MM 细胞，并对其内源蛋白进行标记，以促进全基因组研究。KDM6A 与与免疫识别和细胞因子信号相关的基因结合。最重要的是，KDM6A 结合并激活 NLRC5 和 CIITA，它们分别编码主要组织相容性复合体基因的调节剂。患者数据表明，在 KDM6A 表达水平较低的 MM 中，NLRC5 和 CIITA 下调。染色质分析表明，KDM6A 结合了处于静止和活跃状态的增强子，而 KDM6A 的缺失导致增强子上的 H3K27ac 减少、KDM6A 结合的基因的 H3K27me3 水平增加，以及基因表达减少。用 HDAC3 抑制剂重建组蛋白乙酰化导致主要组织相容性复合体表达上调，为恢复 KDM6A 缺陷肿瘤的免疫原性提供了一种策略。Kirsten 鼠肉瘤病毒（K-RAS）转化的鼠成纤维细胞中 Kdm6a 的缺失导致体内生长增加，与 T 细胞浸润减少相关。
