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 language | English (US) |
|---|---|
| Pages (from-to) | 370-387 |
| Number of pages | 18 |
| Journal | Blood cancer discovery |
| Volume | 2 |
| Issue number | 4 |
| DOIs | |
| State | Published - Jul 1 2021 |
Funding
H. Ohguchi reports grants from Japan Society for the Promotion of Science KAKENHI (1 8 H 0 6 1 6 7 and 1 9 K 2 1 2 7 6), Mochida Memorial Foundation for Medical and Pharmaceutical Research, Shin-nihon Foundation of Advanced Medical Treatment Research, Princess Takamatsu Cancer Research Fund (18–25002), Kobayashi Foundation for Cancer Research, Ichiro Kanehara Foundation for the Promotion of Medical Sciences and Medical Care, Japanese Society of Myeloma Research Award, Japanese Society of Hematology Research Grant, and the program of the Joint Usage/Research Center for Developmental Medicine, Institute of Molecular Embryology and Genetics, Kuma-moto University during the conduct of the study. Y. Kawano reports personal fees from Janssen Pharmaceuticals, Sanofi, Takeda Pharmaceutical Company Limited, and Ono Pharmaceutical CO., LTD. outside the submitted work. N.C. Munshi reports other support from Bristol Myers Squibb, Janssen, Amgen, Takeda, Oncopep, AbbVie, Karyopharm, Novartis, and Legend outside the submitted work. M. Nakao reports grants from Japan Society for the Promotion of Science and Japan Agency for Medical Research and Development during the conduct of the study. U. Oppermann reports nonfinancial support from Oxford NIHR BRC during the conduct of the study, as well as grants from Leducq Foundation, Cancer Research UK, Arthritis Research UK, Bristol Myers Squibb, Bayer Healthcare, and Innovate UK outside the submitted work. A.D. Durbin reports grants from NCI, Damon Runyon Cancer Research Foundation, Rally Foundation for Childhood Cancer Research, Alex’s Lemonade Stand Foundation, and CureSearch for Childhood Cancer Research during the conduct of the study. K.C. Anderson reports personal fees from Pfizer, AstraZeneca, Precision Biosciences, Windmill, Janssen, Starton, C4 Therapeutics, Oncopep, Raqia, and Mana Therapeutics outside the submitted work. J. Qi reports grants from Leukemia & Lymphoma Society and NIH during the conduct of the study; other support from Epiphanes outside the submitted work; and a patent for PCT/US2019/045259 pending. No disclosures were reported by the other authors. The authors thank Hitoshi Takizawa, Goro Sashida, Bob Roader, and Toshio Suda for helpful suggestions and discussions. They thank the Liaison Laboratory Research Promotion Center, Institute of Molecular Embryology and Genetics, Kumamoto University for assistance with ChIP-seq and RNA-seq analyses; the International Research Center for Medical Sciences, Kumamoto University for help with MOLP-8 TurboGFP-Luc cell sorting; the Center for Cancer Computational Biology, Dana-Farber Cancer Institute for assistance with RNA-seq analysis; the Animal Resources Facility, Dana-Farber Cancer Institute for support with animal studies; and the PRISM program at Broad Institute for support on profiling JQKD82 in a panel of 767 cancer cell lines. The authors also thank Charles Lin and Jošt Vrabič Koren for the ERCC spike-in per cell normalization algorithm. They thank Vineela Gangalapudi and Sivasish Sindiri for assistance with constructing the ERCC spike-in RNA-seq pipeline. They thank David Milewski and Young Song for assistance with ChIP-Rx. This research was supported by the Japan Society for the Promotion of Science grants KAKENHI (1 8 H 0 6 1 6 7 and 1 9 K 2 1 2 7 6, to H. Ohguchi), grants from Mochida Memorial Foundation for Medical and Pharmaceutical Research (to H. Ohguchi), the Shinnihon Foundation of Advanced Medical Treatment Research (to H. Ohguchi), the Princess Takamatsu Cancer Research Fund (18–25002; to H. Ohguchi), Kobayashi Foundation for Cancer Research (to H. Ohguchi), the Ichiro Kanehara Foundation for the Promotion of Medical Sciences and Medical Care (to H. Ohguchi), Japanese Society of Myeloma Research Award (to H. Ohguchi), Japanese Society of Hematology Research Grant (to H. Ohguchi), the program of the Joint Usage/Research Center for Developmental Medicine, Institute of Molecular Embryology and Genetics, Kumamoto University (to H. Ohguchi), International Research Center for Medical Sciences grant for international collaborative research (to H. Ohguchi), Dana-Farber/Harvard Cancer Center SPORE in Multiple Myeloma Career Enhancement Award (to H. Ohguchi), NIH training grant 5T32CA236754 (to X. Zhang), Cancer Research UK grant C41580/ A23900 (to U. Oppermann), the LEAN program grant from the Leducq Foundation (to U. Oppermann), NIH grant 5P50CA100707 (to K.C. Anderson), grants from the Paula and Rodger Riney Foundation (to K.C. Anderson), NIH grant R01CA233601 (to J. Qi), and a Leukemia & Lymphoma Society TRP grant (to J. Qi). A.D. Durbin is the recipient of a Damon Runyon-Sohn Fellowship and funding from the Alex’s Lemonade Stand Foundation, CureSearch for Children’s Cancer foundation, and the American Lebanese Syrian Associated Charities.
ASJC Scopus subject areas
- General Medicine
