NSD2 dimethylation at H3K36 promotes lung adenocarcinoma pathogenesis.

Autor: Sengupta D; Department of Biology, Stanford University, Stanford, CA 94305, USA., Zeng L; Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Li Y; Division of Computational Biomedicine, Department of Biological Chemistry, School of Medicine, University of California, Irvine, Irvine, CA 92697, USA., Hausmann S; Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Ghosh D; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA., Yuan G; Department of Biology, Stanford University, Stanford, CA 94305, USA., Nguyen TN; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA., Lyu R; Department of Chemistry, The University of Chicago, Chicago, IL 60637, USA., Caporicci M; Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Morales Benitez A; Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Coles GL; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA., Kharchenko V; Division of Biological and Environmental Science and Engineering, King Abdullah University of Science and Technology, Thuwal 23955-6900, Saudi Arabia., Czaban I; Division of Biological and Environmental Science and Engineering, King Abdullah University of Science and Technology, Thuwal 23955-6900, Saudi Arabia., Azhibek D; Division of Biological and Environmental Science and Engineering, King Abdullah University of Science and Technology, Thuwal 23955-6900, Saudi Arabia., Fischle W; Division of Biological and Environmental Science and Engineering, King Abdullah University of Science and Technology, Thuwal 23955-6900, Saudi Arabia., Jaremko M; Division of Biological and Environmental Science and Engineering, King Abdullah University of Science and Technology, Thuwal 23955-6900, Saudi Arabia., Wistuba II; Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Sage J; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA., Jaremko Ł; Division of Biological and Environmental Science and Engineering, King Abdullah University of Science and Technology, Thuwal 23955-6900, Saudi Arabia., Li W; Division of Computational Biomedicine, Department of Biological Chemistry, School of Medicine, University of California, Irvine, Irvine, CA 92697, USA. Electronic address: wei.li@uci.edu., Mazur PK; Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: pkmazur@mdanderson.org., Gozani O; Department of Biology, Stanford University, Stanford, CA 94305, USA. Electronic address: ogozani@stanford.edu.
Jazyk: angličtina
Zdroj: Molecular cell [Mol Cell] 2021 Nov 04; Vol. 81 (21), pp. 4481-4492.e9. Date of Electronic Publication: 2021 Sep 22.
DOI: 10.1016/j.molcel.2021.08.034
Abstrakt: The etiological role of NSD2 enzymatic activity in solid tumors is unclear. Here we show that NSD2, via H3K36me2 catalysis, cooperates with oncogenic KRAS signaling to drive lung adenocarcinoma (LUAD) pathogenesis. In vivo expression of NSD2 E1099K , a hyperactive variant detected in individuals with LUAD, rapidly accelerates malignant tumor progression while decreasing survival in KRAS-driven LUAD mouse models. Pathologic H3K36me2 generation by NSD2 amplifies transcriptional output of KRAS and several complementary oncogenic gene expression programs. We establish a versatile in vivo CRISPRi-based system to test gene functions in LUAD and find that NSD2 loss strongly attenuates tumor progression. NSD2 knockdown also blocks neoplastic growth of PDXs (patient-dervived xenografts) from primary LUAD. Finally, a treatment regimen combining NSD2 depletion with MEK1/2 inhibition causes nearly complete regression of LUAD tumors. Our work identifies NSD2 as a bona fide LUAD therapeutic target and suggests a pivotal epigenetic role of the NSD2-H3K36me2 axis in sustaining oncogenic signaling.
Competing Interests: Declaration of interests O.G. is a co-scientific founder, consultant, and stockholder of EpiCypher, Inc. and K36 Therapeutics, Inc. P.K.M. is a scientific co-founder, consultant, and stockholder of Amplified Medicines, Inc. and Ikena Oncology, Inc.
(Copyright © 2021 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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