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Elevated NSD3 histone methylation activity drives squamous cell lung cancer
Yuan,Gang1; Flores,Natasha M.2; Hausmann,Simone2; Lofgren,Shane M.2; Kharchenko,Vladlena3; Angulo-Ibanez,Maria4,5; Sengupta,Deepanwita1; Lu,Xiaoyin2; Czaban,Iwona3; Azhibek,Dulat3; Vicent,Silvestre6; Fischle,Wolfgang3; Jaremko,Mariusz3; Fang,Bingliang7; Wistuba,Ignacio I.8; Chua,Katrin F.4,5; Roth,Jack A.7; Minna,John D.9,10,11; Shao,Ning Yi12; Jaremko,Łukasz3; Mazur,Pawel K.2; Gozani,Or1
2021
Source PublicationNature
ISSN0028-0836
Abstract

Amplification of chromosomal region 8p11–12 is a common genetic alteration that has been implicated in the aetiology of lung squamous cell carcinoma (LUSC). The FGFR1 gene is the main candidate driver of tumorigenesis within this region. However, clinical trials evaluating FGFR1 inhibition as a targeted therapy have been unsuccessful. Here we identify the histone H3 lysine 36 (H3K36) methyltransferase NSD3, the gene for which is located in the 8p11–12 amplicon, as a key regulator of LUSC tumorigenesis. In contrast to other 8p11–12 candidate LUSC drivers, increased expression of NSD3 correlated strongly with its gene amplification. Ablation of NSD3, but not of FGFR1, attenuated tumour growth and extended survival in a mouse model of LUSC. We identify an LUSC-associated variant NSD3(T1232A) that shows increased catalytic activity for dimethylation of H3K36 (H3K36me2) in vitro and in vivo. Structural dynamic analyses revealed that the T1232A substitution elicited localized mobility changes throughout the catalytic domain of NSD3 to relieve auto-inhibition and to increase accessibility of the H3 substrate. Expression of NSD3(T1232A) in vivo accelerated tumorigenesis and decreased overall survival in mouse models of LUSC. Pathological generation of H3K36me2 by NSD3(T1232A) reprograms the chromatin landscape to promote oncogenic gene expression signatures. Furthermore, NSD3, in a manner dependent on its catalytic activity, promoted transformation in human tracheobronchial cells and growth of xenografted human LUSC cell lines with amplification of 8p11–12. Depletion of NSD3 in patient-derived xenografts from primary LUSCs containing NSD3 amplification or the NSD3(T1232A)-encoding variant attenuated neoplastic growth in mice. Finally, NSD3-regulated LUSC-derived xenografts were hypersensitive to bromodomain inhibition. Thus, our work identifies NSD3 as a principal 8p11–12 amplicon-associated oncogenic driver in LUSC, and suggests that NSD3-dependency renders LUSC therapeutically vulnerable to bromodomain inhibition.

DOI10.1038/s41586-020-03170-y
URLView the original
Indexed BySCIE
Language英語English
WOS Research AreaScience & Technology - Other Topics
WOS SubjectMultidisciplinary Sciences
WOS IDWOS:000614414900009
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Cited Times [WOS]:3   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionFaculty of Health Sciences
Corresponding AuthorGozani,Or
Affiliation1.Department of Biology,Stanford University,Stanford,United States
2.Department of Experimental Radiation Oncology,The University of Texas MD Anderson Cancer Center,Houston,United States
3.Division of Biological and Environmental Science and Engineering,King Abdullah University of Science and Technology,Thuwal,Saudi Arabia
4.Department of Medicine,Stanford University School of Medicine,Stanford,United States
5.Geriatric Research,Education,and Clinical Center,Veterans Affairs Palo Alto Health Care System,Palo Alto,United States
6.University of Navarra,Center for Applied Medical Research,Pamplona,Spain
7.Department of Thoracic and Cardiovascular Surgery,The University of Texas MD Anderson Cancer Center,Houston,United States
8.Department of Translational Molecular Pathology,The University of Texas MD Anderson Cancer Center,Houston,United States
9.Hamon Center for Therapeutic Oncology Research,University of Texas Southwestern Medical Center,Dallas,United States
10.Department of Internal Medicine,University of Texas Southwestern Medical Center,Dallas,United States
11.Department of Pharmacology,University of Texas Southwestern Medical Center,Dallas,United States
12.Faculty of Health Sciences,University of Macau,Macao
Recommended Citation
GB/T 7714
Yuan,Gang,Flores,Natasha M.,Hausmann,Simone,et al. Elevated NSD3 histone methylation activity drives squamous cell lung cancer[J]. Nature,2021.
APA Yuan,Gang.,Flores,Natasha M..,Hausmann,Simone.,Lofgren,Shane M..,Kharchenko,Vladlena.,Angulo-Ibanez,Maria.,Sengupta,Deepanwita.,Lu,Xiaoyin.,Czaban,Iwona.,Azhibek,Dulat.,Vicent,Silvestre.,Fischle,Wolfgang.,Jaremko,Mariusz.,Fang,Bingliang.,Wistuba,Ignacio I..,Chua,Katrin F..,Roth,Jack A..,Minna,John D..,Shao,Ning Yi.,...&Gozani,Or.(2021).Elevated NSD3 histone methylation activity drives squamous cell lung cancer.Nature.
MLA Yuan,Gang,et al."Elevated NSD3 histone methylation activity drives squamous cell lung cancer".Nature (2021).
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