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Effects of NSD2 depletion on gene expression and H3K36me2 in a lung cancer cell line

ABSTRACT: The histone methyltransferase NSD2/WHSC1/MMSET is overexpressed in a number of solid tumors but its contribution to the biology of these tumors is not well understood. Here, we describe that NSD2 contributes to the proliferation of a subset of lung cancer cell lines by supporting oncogenic RAS transcriptional responses. Co-treatment with MEK and BRD4 inhibitors causes co-operative inhibitory responses on cell growth. While these inhibitors converge in the downregulation of genes associated with cancer-acquired super-enhancers, NSD2 inhibition complements their action by affecting the expression of clusters of genes embedded in megabase-scale regions marked with H3K36me2. Thus, combinatorial therapies using MEK or BRD4 inhibitors together with NSD2 inhibition ensure a more comprehensive inhibition of oncogenic RAS-driven transcription programs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE73696 | GEO | 2017/02/14

SECONDARY ACCESSION(S): PRJNA297680

REPOSITORIES: GEO

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Transcriptome analysis of NSD2/WHSC1/MMSET-depleted human fibroblast cells

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Project description:NSD2 (also named MMSET and WHSC1) is a histone lysine methyltransferase that is implicated in diverse diseases and commonly overexpressed in multiple myeloma due to a recurrent t(4;14) chromosomal translocation. However, the precise catalytic activity of NSD2 is obscure, preventing progress in understanding how this enzyme influences chromatin biology and myeloma pathogenesis. Here we show that dimethylation of histone H3 at lysine 36 (H3K36me2) is the principal chromatin-regulatory activity of NSD2. Catalysis of H3K36me2 by NSD2 is sufficient for gene activation. In t(4;14)-positive myeloma cells, the normal genome-wide and gene-specific distribution of H3K36me2 is obliterated, creating a chromatin landscape that selects for a transcription profile favorable for myelomagenesis. Catalytically active NSD2 confers xenograft tumor formation and invasion capacity upon t(4;14)-negative cells and NSD2 promotes oncogenic transformation of primary cells in an H3K36me2-dependent manner. Together our findings establish H3K36me2 as the primary product generated by NSD2, and demonstrate that genomic disorganization of this canonical chromatin mark initiates oncogenic programming. Genome-wide expression profiling of p19ARF-/- mouse embryonic fibroblasts stably transduced with control vector or wild-type NSD2. Each cell line is tested in triplicate.

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