NSD2 contributes to oncogenic RAS-driven transcription in lung cancer cells through long-range epigenetic activation.
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.
CNIO-Lilly Epigenetics Laboratory, Spanish National Cancer Research Center (CNIO), C/ Melchor Fernández Almagro, 3. 28029 Madrid, Spain.
Verónica
V
García-Carpizo
CNIO-Lilly Epigenetics Laboratory, Spanish National Cancer Research Center (CNIO), C/ Melchor Fernández Almagro, 3. 28029 Madrid, Spain.
Jacinto
J
Sarmentero
Eli Lilly and Company, 46285 Indianapolis, USA.
Bomie
B
Han
Structural Biology and Biocomputing Program, Spanish National Cancer Research Center (CNIO), C/ Melchor Fernández Almagro, 3. 28029 Madrid, Spain.
Osvaldo
O
Graña
CNIO-Lilly Epigenetics Laboratory, Spanish National Cancer Research Center (CNIO), C/ Melchor Fernández Almagro, 3. 28029 Madrid, Spain.
Sergio
S
Ruiz-Llorente
Structural Biology and Biocomputing Program, Spanish National Cancer Research Center (CNIO), C/ Melchor Fernández Almagro, 3. 28029 Madrid, Spain.
David G
DG
Pisano
Molecular Oncology Program, Spanish National Cancer Research Center (CNIO), C/Melchor Fernández Almagro, 3. 28029 Madrid, Spain.
Manuel
M
Serrano
Eli Lilly and Company, 46285 Indianapolis, USA.
Harold B
HB
Brooks
Eli Lilly and Company, 46285 Indianapolis, USA.
Robert M
RM
Campbell
CNIO-Lilly Epigenetics Laboratory, Spanish National Cancer Research Center (CNIO), C/ Melchor Fernández Almagro, 3. 28029 Madrid, Spain.
Maria J
MJ
Barrero
D000818:Animals; D001381:Azepines / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004159:Diphenylamine / Q000031:analogs & derivatives / Q000494:pharmacology; D004742:Enhancer Elements, Genetic; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044127:Epigenesis, Genetic; D015870:Gene Expression / Q000187:drug effects; D055785:Gene Knockdown Techniques; D011905:Genes, ras; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics*; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors; D008745:Methylation; D051379:Mice; D008819:Mice, Nude; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000037:antagonists & inhibitors; D014158:Transcription, Genetic; D014230:Triazoles / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D000092468:Bromodomain Containing Proteins
D001381:Azepines; D001549:Benzamides; D018797:Cell Cycle Proteins; D004159:Diphenylamine; D004791:Enzyme Inhibitors; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones; D020930:MAP Kinase Kinase Kinases; D009687:Nuclear Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D014230:Triazoles; C561695:(+)-JQ1 compound; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C506614:mirdametinib; C419586:NSD2 protein, human