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

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Lysine demethylase 5A (KDM5A) is a negative regulator of histone H3 lysine 4 trimethy-lation (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 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 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. SIGNIFICANCE: We delineate the function of KDM5A in activating the MYC-driven transcriptional landscape. We develop a cell-permeable KDM5 inhibitor to define the activating role of KDM5A on MYC target gene expression and implicate the therapeutic potential of this compound in mouse models and multiple myeloma patient samples.See related video from the AACR Annual Meeting 2021: https://vimeo.com/554896826.

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

ASJC Scopus subject areas

  • Oncology

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