| Literature DB >> 34258103 |
Hiroto Ohguchi1, Paul M C Park2, Tingjian Wang2, Berkley E Gryder3,4, Daisuke Ogiya5, Keiji Kurata5, Xiaofeng Zhang2, Deyao Li2, Chengkui Pei2, Takeshi Masuda6, Catrine Johansson7, Virangika K Wimalasena2, Yong Kim3, Shinjiro Hino8, Shingo Usuki9, Yawara Kawano10, Mehmet K Samur5, Yu-Tzu Tai5, Nikhil C Munshi5, Masao Matsuoka10, Sumio Ohtsuki6, Mitsuyoshi Nakao8, Takashi Minami11, Shannon Lauberth12, Javed Khan3, Udo Oppermann7,13, Adam D Durbin14, Kenneth C Anderson15,16, Teru Hideshima15, Jun Qi17,16.
Abstract
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 in vitro and in vivo. 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.Entities:
Keywords: Epigenetics; Histone modifications; JQKD82; KDM5 inhibitor; Multiple myeloma; Transcription factor
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Year: 2021 PMID： 34258103 PMCID： PMC8265280 DOI： 10.1158/2643-3230.BCD-20-0108
Source DB: PubMed Journal: Blood Cancer Discov ISSN： 2643-3230