Elevated NSD3 histone methylation activity drives squamous cell lung cancer

Amplifcation 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 amplifcation. 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 amplifcation of 8p11–12. Depletion of NSD3 in patient-derived xenografts from primary LUSCs containing NSD3 amplifcation 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 identifes NSD3 as a principal 8p11–12 amplicon-associated oncogenic driver in LUSC, and suggests that NSD3-dependency renders LUSC therapeutically vulnerable to bromodomain inhibition.

Yuan, G., Flores, N. M., Hausmann, S., Lofgren, S. M., Kharchenko, V., Angulo-Ibanez, M., … Gozani, O. (2021). Elevated NSD3 histone methylation activity drives squamous cell lung cancer. Nature. doi:10.1038/s41586-020-03170-y

We thank members of the Gozani and Mazur laboratories for critical reading of the manuscript, and M. Lin for the AkaLuc vector. This work was supported in part by grants from the NIH to O.G. (R01 GM079641 and R35 GM139569), K.F.C. (R01AG050997) and P.K.M. (R00 CA197816), 1U54CA224065 to B.F. and J.A.R., VA Merit Award to K.F.C., intramural funds from KAUST to W.F., Ł.J. and M.J., the P. Neuroendocrine Tumor Research Foundation, AACR, DOD PRCRP Career Development Award (CA181486), Career Enhancement Grant – The University of Texas NIH SPORE in Lung Cancer (P50CA070907), and the Andrew Sabin Family Foundation Scientist and CPRIT Scholar in Cancer Research (RR160078) to P.K.M. N.-Y.S. was supported by SRG2019-00177-FHS and FDCT0038/2020/AFJ, N.M.F. by the American Cancer Society – Joe & Jessie Crump Foundation Fellowship (PF-20-108-01-DMC), X.L. by a CPRIT Research Training Grant (RP170067) and S.H. by a Deutsche Forschungsge meinschaft Fellowship (HA8434/1-1).

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