Division of Disease Epigenetics, Institute of Resource Development and Analysis, Kumamoto University, Kumamoto, Japan.
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Blood Cancer Discov. 2021 Jul;2(4):370-387. doi: 10.1158/2643-3230.BCD-20-0108. Epub 2021 Apr 10.
Lysine demethylase 5A (KDM5A) is a negative regulator of histone H3K4 trimethylation, a histone mark associated with activate gene transcription. We identify that KDM5A interacts with the P-TEFb complex and cooperates with MYC to control MYC targeted genes in multiple myeloma (MM) cells. We develop a cell-permeable and selective KDM5 inhibitor, JQKD82, that increases histone H3K4me3 but paradoxically inhibits downstream MYC-driven transcriptional output and . Using genetic ablation together with our inhibitor, we establish that KDM5A supports MYC target gene transcription independent of MYC itself, by supporting TFIIH (CDK7)- and P-TEFb (CDK9)-mediated phosphorylation of RNAPII. These data identify KDM5A as a unique vulnerability in MM functioning through regulation of MYC-target gene transcription, and establish JQKD82 as a tool compound to block KDM5A function as a potential therapeutic strategy for MM.
赖氨酸去甲基化酶 5A（KDM5A）是组蛋白 H3K4 三甲基化的负调控因子，是与激活基因转录相关的组蛋白标记。我们发现 KDM5A 与 P-TEFb 复合物相互作用，并与 MYC 合作，在多发性骨髓瘤（MM）细胞中控制 MYC 靶向基因。我们开发了一种细胞通透性和选择性的 KDM5 抑制剂 JQKD82，它增加组蛋白 H3K4me3，但矛盾地抑制下游 MYC 驱动的转录产物。利用遗传消融和我们的抑制剂，我们确定 KDM5A 通过支持 TFIIH（CDK7）-和 P-TEFb（CDK9）介导的 RNAPII 磷酸化，独立于 MYC 本身，支持 MYC 靶基因转录。这些数据表明 KDM5A 通过调节 MYC 靶基因转录成为 MM 功能的独特弱点，并确立 JQKD82 作为一种阻断 KDM5A 功能的工具化合物，作为 MM 的潜在治疗策略。
