Elevated NSD3 histone methylation activity drives squamous cell lung cancer

Gang Yuan, Natasha M. Flores, Simone Hausmann, Shane M. Lofgren, Vladlena Kharchenko, Maria Angulo-Ibanez, Deepanwita Sengupta, Xiaoyin Lu, Iwona Czaban, Dulat Azhibek, Silvestre Vicent, Wolfgang Fischle, Mariusz Jaremko, Bingliang Fang, Ignacio I. Wistuba, Katrin F. Chua, Jack A. Roth, John D. Minna, Ning-Yi Shao (), Łukasz Jaremko (), Pawel K. Mazur () and Or Gozani ()
Additional contact information
Gang Yuan: Stanford University
Natasha M. Flores: The University of Texas MD Anderson Cancer Center
Simone Hausmann: The University of Texas MD Anderson Cancer Center
Shane M. Lofgren: The University of Texas MD Anderson Cancer Center
Vladlena Kharchenko: King Abdullah University of Science and Technology
Maria Angulo-Ibanez: Stanford University School of Medicine
Deepanwita Sengupta: Stanford University
Xiaoyin Lu: The University of Texas MD Anderson Cancer Center
Iwona Czaban: King Abdullah University of Science and Technology
Dulat Azhibek: King Abdullah University of Science and Technology
Silvestre Vicent: University of Navarra, Center for Applied Medical Research
Wolfgang Fischle: King Abdullah University of Science and Technology
Mariusz Jaremko: King Abdullah University of Science and Technology
Bingliang Fang: The University of Texas MD Anderson Cancer Center
Ignacio I. Wistuba: The University of Texas MD Anderson Cancer Center
Katrin F. Chua: Stanford University School of Medicine
Jack A. Roth: The University of Texas MD Anderson Cancer Center
John D. Minna: University of Texas Southwestern Medical Center
Ning-Yi Shao: University of Macau
Łukasz Jaremko: King Abdullah University of Science and Technology
Pawel K. Mazur: The University of Texas MD Anderson Cancer Center
Or Gozani: Stanford University

Nature, 2021, vol. 590, issue 7846, 504-508

Abstract: 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)1–3. The FGFR1 gene is the main candidate driver of tumorigenesis within this region4. However, clinical trials evaluating FGFR1 inhibition as a targeted therapy have been unsuccessful5. 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.

Date: 2021
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DOI: 10.1038/s41586-020-03170-y

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