Elevated NSD3 Histone Methylation Activity Drives Squamous Cell Lung Cancer

ABSTRACT: Amplification of chromosomal region 8p11-12 is a frequent genetic alteration implicated in the etiology of lung squamous cell carcinoma (LUSC). FGFR1 (fibroblast growth factor receptor 1) is the main candidate driver within this region. However, clinical trials evaluating FGFR1 inhibition as a targeted therapy have been unsuccessful. Here we identify the H3K36 methyltransferase NSD3 (nuclear receptor binding SET domain protein 3), an 8p11-12-localized gene, as a key regulator of LUSC tumorigenesis. In contrast to other 8p11-12 candidate LUSC drivers, increased NSD3 expression strongly correlates with gene amplification. Ablation of NSD3, but not FGFR1, attenuates tumor growth and extends survival in a potent LUSC mouse model. We identify NSD3T1232A as an LUSC-associated variant that increases H3K36 dimethylation (H3K36me2) catalytic activity in vitro and in vivo. Structural dynamic analyses reveal that the T1232A substitution elicits localized mobility changes throughout NSD3’s catalytic domain to relieve auto-inhibition and increase H3 substrate accessibility. NSD3T1232A expression in vivo in LUSC mouse models accelerates tumorigenesis and decreases overall survival. Pathologic generation of H3K36me2 by NSD3T1232A rewires the chromatin landscape to promote oncogenic gene expression programming. Accordingly, depletion of NSD3 and H3K36me2 in patient derived xenografts (PDXs) from primary LUSC harboring NSD3 amplification or the NSD3T1232A variant attenuate neoplastic growth. Finally, NSD3-regulated LUSC PDXs are markedly and selectively sensitive to bromodomain inhibition (BETi). Together, 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 BETi.

ORGANISM(S): Mus musculus

PROVIDER: GSE149272 | GEO | 2020/11/24

REPOSITORIES: GEO