Lysine Demethylase 5A is Required for MYC Driven Transcription in Multiple Myeloma.

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.

• Authors: 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 Matsuoka, Sumio Ohtsuki, Mitsuyoshi Nakao, Takashi Minami, Shannon Lauberth, Javed Khan, Udo Oppermann, Adam D Durbin, Kenneth C Anderson, Teru Hideshima, Jun Qi
• Journal: Blood cancer discovery (Blood Cancer Discov) Vol. 2 Issue 4 Pg. 370-387 (07 2021) ISSN: 2643-3249 [Electronic] United States
• PMID: 34258103 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• MYC protein, human
• Proto-Oncogene Proteins c-myc
• KDM5A protein, human
• Retinoblastoma-Binding Protein 2
• Cyclin-Dependent Kinase 9
• Cyclin-Dependent Kinases
• RNA Polymerase II
• Lysine
• Cyclin-Dependent Kinase-Activating Kinase
• CDK7 protein, human

Topics

• Cyclin-Dependent Kinase 9 (metabolism)
• Cyclin-Dependent Kinases (metabolism)
• Genes, cdc
• Humans
• Lysine
• Methylation
• Multiple Myeloma (genetics)
• Proto-Oncogene Proteins c-myc (genetics)
• RNA Polymerase II
• Retinoblastoma-Binding Protein 2
• Cyclin-Dependent Kinase-Activating Kinase