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Sci Rep. 2016 Sep 8;6:32952. doi: 10.1038/srep32952.

NSD2 contributes to oncogenic RAS-driven transcription in lung cancer cells through long-range epigenetic activation.

Author information

1
CNIO-Lilly Epigenetics Laboratory, Spanish National Cancer Research Center (CNIO), C/ Melchor Fernández Almagro, 3. 28029 Madrid, Spain.
2
Eli Lilly and Company, 46285 Indianapolis, USA.
3
Structural Biology and Biocomputing Program, Spanish National Cancer Research Center (CNIO), C/ Melchor Fernández Almagro, 3. 28029 Madrid, Spain.
4
Molecular Oncology Program, Spanish National Cancer Research Center (CNIO), C/Melchor Fernández Almagro, 3. 28029 Madrid, Spain.

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. NSD2 knock down combined with MEK or BRD4 inhibitors causes co-operative inhibitory responses on cell growth. However, while MEK and BRD4 inhibitors converge in the downregulation of genes associated with cancer-acquired super-enhancers, NSD2 inhibition affects the expression of clusters of genes embedded in megabase-scale regions marked with H3K36me2 and that contribute to the RAS transcription program. Thus, combinatorial therapies using MEK or BRD4 inhibitors together with NSD2 inhibition are likely to be needed to ensure a more comprehensive inhibition of oncogenic RAS-driven transcription programs in lung cancers with NSD2 overexpression.

PMID:
27604143
PMCID:
PMC5015087
DOI:
10.1038/srep32952
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

This work was supported by Eli Lilly and Company. B.H., H.B.B. and R.M.C. are employees of Eli Lilly and Company.

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