Heterochromatin fidelity is a therapeutic vulnerability in lymphoma and other human cancers
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| Publicado en: | bioRxiv (Feb 5, 2025) |
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| Autor principal: | |
| Otros Autores: | , , , , , , , , , , , , , , , , , , , , , , , , , |
| Publicado: |
Cold Spring Harbor Laboratory Press
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| Materias: | |
| Acceso en línea: | Citation/Abstract Full text outside of ProQuest |
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| Resumen: | Genes involved in the regulation of chromatin structure are frequently disrupted in cancer, contributing to an aberrant transcriptome and phenotypic plasticity. Yet, therapeutics targeting mutant forms of chromatin-modifying enzymes have yielded only modest clinical utility, underscoring the difficulty of targeting the epigenomic underpinnings of aberrant gene regulatory networks. Here, we sought to identify novel epigenetic vulnerabilities in diffuse large B-cell lymphoma (DLBCL). Through phenotypic screens and biochemical analysis, we demonstrated that inhibition of the H3K9 demethylases KDM4A and KDM4C elicits potent, subtype-agnostic cytotoxicity by antagonizing transcriptional networks associated with B-cell identity and epigenetically rewiring heterochromatin. KDM4 demethylases associated with the KRAB zinc finger ZNF587, and their enzymatic inhibition led to DNA replication stress and DNA damage-induced cGAS-STING activation. Broad surveys of transcriptional data from patients also revealed KDM4 family dysregulation in several other cancer types. To explore this potential therapeutic avenue, we performed high-throughput small molecule screens with H3K9me3 nucleosome substrates and identified novel KDM4 demethylase inhibitors. AI-guided protein-ligand binding predictions suggested diverse modes of action for various small molecule hits. Our findings underscore the relevance of targeting fundamental transcriptional and epigenetic mechanisms for anti-cancer therapy.Competing Interest StatementMN, DKJ, and GQD are named inventors on several patent applications related to this work filed by Boston Children's Hospital. DKJ is now a full-time employee of Merck & Co., Inc. YCH is now a full-time employee of Takeda Pharmaceuticals. GQD holds equity in Redona Therapeutics, Inc. PCB serves as a consultant to or equity holder in several companies including 10X Technologies/10X Genomics, GALT/Isolation Bio, Next Gen Diagnostics, Cache DNA, Concerto Biosciences, Stately Bio, Ramona Optics, Bifrost Biosystems, and Amber Bio. PCB's lab has received funding from Calico Life Sciences, Merck & Co., Inc., and Genentech for unrelated research. YS is a consultant/advisor of the Institute of Biomedical Sciences, Fudan University, a consultant for Bioduro, an equity holder in Imago Biosciences and Active Motif, a co-founder/equity holder of Constellation Pharmaceuticals, Inc., and a consultant for Guangzhou BeBetter Medicine Technology Co., LTD. MRM, AV, ZBG, SAH, and MCK own shares in EpiCypher Inc. MCK serves on the board of directors of EpiCypher Inc. EpiCypher is a commercial developer and supplier of reagents used in this study (including synthetic histone peptides and fully defined semi-synthetic nucleosomes). |
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| ISSN: | 2692-8205 |
| DOI: | 10.1101/2025.01.31.635709 |
| Fuente: | Biological Science Database |