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) 1 - 3 . FGFR1 (fibroblast growth factor receptor 1) is the main candidate driver within this region 4 . However, clinical trials evaluating FGFR1 inhibition as a targeted therapy have been unsuccessful 5 . Here we identify the H3K36 methyltransferase NSD3 ( n uclear receptor binding S ET d omain 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 its gene amplification. Ablation of NSD3 , but not FGFR1 , attenuates tumor growth and extends survival in a potent LUSC mouse model. We identify NSD3 T1232A 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. NSD3 T1232A expression in vivo accelerates tumorigenesis and decreases overall survival in LUSC mouse models. Pathologic H3K36me2 generation by NSD3 T1232A rewires the chromatin landscape to promote oncogenic gene expression programming. Further, NSD3’s catalytic activity promotes human tracheobronchial cell transformation and xenograft growth of human 8p11-12-amplified LUSC cell lines. NSD3 depletion in patient-derived xenografts (PDXs) from primary LUSC harboring NSD3 amplification or the NSD3 T1232A variant attenuates neoplastic growth. Finally, NSD3-regulated LUSC PDXs are markedly 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.

Targeting H3K36 methyltransferases NSDs: a promising strategy for tumor targeted therapy

“…Through analyzing the genetic alterations and mRNA expression of NSD3 in LUSC datasets from The Cancer Genome Atlas (TCGA) and human LUSC cell lines as well as patient-derived xenograft (PDX) samples, Yuan et al found that NSD3 overexpression could be observed in ~60% of LUSC samples, 20% of which contain 8p11-12 amplification. 1 In addition, the gain-of-function (GOF) variant NSD3 (T1232A) was also detected in LUSC samples, though it is not as common as NSD3 amplification (Fig. 1 ).…”

“…Recently, two studies published in Nature identified genetic changes in the nuclear receptor-binding SET domain protein (NSD) family of histone methyltransferases as oncogenic drivers in some malignancies, and revealed the nucleosome-based recognition and histone-modification mechanisms of NSD2 and NSD3. 1 , 2 …”

“…The study by Yuan et al identified H3K36 methyltransferase NSD3, rather than FGFR1, as an oncogenic driver within the 8p11-12 amplicon in LUSC. 1 The authors established a mouse LUSC model harboring canonical LUSC alterations co-occurring with 8p11-12 amplification (constitutively active PI3K, overexpression of SOX2, and deletion of CDKN2A and CDKN2B), named PSC mouse LUSC model. Increased NSD3 expression in lungs tracks with the progression of LUSC in this model.…”

An epigenetic tipping point in cancer comes under the microscope

“…One way in which genes are controlled is through the addition of various chemical marks to DNA and DNA-associated proteins. Writing in Nature, Yuan et al 1 and Li et al 2 show that one of the enzymes that deposit such marks, NSD3, is mutated and hyperactive in some human cancers -a finding that suggests new avenues for treating people with the diseases.…”

“…Figure 1 | Deregulation of histone methylation in human cancer.The enzyme NSD3 is a histone methyltransferase -it dimethylates (adds two methyl groups to) histone H3 proteins, around which DNA is packaged. Yuan et al1 have found that NSD3 is dysregulated in human squamous cell lung carcinoma, and Li et al2 have unravelled the structural mechanism involved. a, In 'NSD3-addicted cancers', the enzymatic activity of NSD3 is increased through an increase in the number of copies of the NSD3 gene, or through mutations that cause hyperactive enzyme activity (not shown).…”