The MMSET histone methyl transferase switches global histone methylation and alters gene expression in t(4;14) multiple myeloma cells.
The multiple myeloma SET domain (MMSET) protein is overexpressed in multiple myeloma (MM) patients with the translocation t(4;14). Although studies have shown the involvement of MMSET/Wolf-Hirschhorn syndrome candidate 1 in development, its mode of action in the pathogenesis of MM is largely unknown. We found that MMSET is a major regulator of chromatin structure and transcription in t(4;14) MM cells. High levels of MMSET correlate with an increase in lysine 36 methylation of histone H3 and a decrease in lysine 27 methylation across the genome, leading to a more open structural state of the chromatin. Loss of MMSET expression alters adhesion properties, suppresses growth, and induces apoptosis in MM cells. Consequently, genes affected by high levels of MMSET are implicated in the p53 pathway, cell cycle regulation, and integrin signaling. Regulation of many of these genes required functional histone methyl-transferase activity of MMSET. These results implicate MMSET as a major epigenetic regulator in t(4;14)+ MM.
Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Eva
E
Martinez-Garcia
Relja
R
Popovic
Dong-Joon
DJ
Min
Steve M M
SM
Sweet
Paul M
PM
Thomas
Leonid
L
Zamdborg
Aaron
A
Heffner
Christine
C
Will
Laurence
L
Lamy
Louis M
LM
Staudt
David L
DL
Levens
Neil L
NL
Kelleher
Jonathan D
JD
Licht
D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002448:Cell Adhesion; D002453:Cell Cycle; D002465:Cell Movement; D049109:Cell Proliferation; D002843:Chromatin / Q000235:genetics; D047369:Chromatin Immunoprecipitation; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics*; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics*; D019175:DNA Methylation; D057890:Epigenomics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D006657:Histones / Q000235:genetics*; D006801:Humans; D009101:Multiple Myeloma / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D020033:Protein Isoforms; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014178:Translocation, Genetic / Q000235:genetics*; D014407:Tumor Cells, Cultured
D014408:Biomarkers, Tumor; D002843:Chromatin; D006657:Histones; D020033:Protein Isoforms; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D011495:Histone-Lysine N-Methyltransferase; C419586:NSD2 protein, human