Lysine Demethylase 5A Is Required for MYC-Driven Transcription in Multiple Myeloma

Hiroto Ohguchi*, Paul M.C. Park, Tingjian Wang, Berkley E. Gryder, Daisuke Ogiya, Keiji Kurata, Xiaofeng Zhang, Deyao Li, Chengkui Pei, Takeshi Masuda, Catrine Johansson, Virangika K. Wimalasena, Yong Kim, Shinjiro Hino, Shingo Usuki, Yawara Kawano, Mehmet K. Samur, Yu Tzu Tai, Nikhil C. Munshi, Masao MatsuokaSumio Ohtsuki, Mitsuyoshi Nakao, Takashi Minami, Shannon Lauberth, Javed Khan, Udo Oppermann, Adam D. Durbin, Kenneth C. Anderson*, Teru Hideshima*, Jun Qi*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

Lysine demethylase 5A (KDM5A) is a negative regulator of histone H3 lysine 4 trimethylation (H3K4me3), 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 cells. We develop a cell-permeable and selective KDM5 inhibitor, JQKD82, that increases H3K4me3 but paradoxically inhibits downstream MYC-driven transcriptional output invitroand invivo. 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 multiple myeloma 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 multiple myeloma.

Original languageEnglish (US)
Pages (from-to)370-387
Number of pages18
JournalBlood cancer discovery
Volume2
Issue number4
DOIs
StatePublished - Jul 1 2021

ASJC Scopus subject areas

  • General Medicine

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