Loss of the SMRT/NCoR2 corepressor correlates with JAG2 overexpression in multiple myeloma.
Multiple myeloma (MM) is a clonal B-cell neoplasm that accounts for 10% of all malignant hematologic neoplasms and that affects terminally differentiated B cells (i.e., plasma cells). It is now well recognized that the cytokine interleukin-6 (IL-6) is a major cytokine that promotes the proliferation of malignant plasma cells in MM. The IL-6 gene can be regulated by the NOTCH genes products. We have previously shown that the NOTCH ligand, JAG2, is overexpressed in MM. To investigate the mechanism(s) leading to JAG2 overexpression in MM, we assessed potential epigenetic modifications of the JAG2 promoter. We showed that the JAG2 promoter region is aberrantly acetylated in MM cell lines and patient samples. The acetylation state of histones is regulated by the recruitment of histone deacetylases (HDAC). HDACs are typically recruited to promoter regions through interaction with nuclear corepressors such as SMRT. SMRT levels were therefore investigated. Interestingly, MM cell lines and patient samples presented significantly reduced SMRT levels. The experiments suggest a correlation between constitutive acetylation of the JAG2 core promoter in the MM cell lines and reduced levels of the SMRT corepressor that recruits HDAC to promoter regions. Finally, SMRT function restoration induced JAG2 down-regulation as well as MM cell apoptosis.
Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
Pushpankur
P
Ghoshal
Alain J
AJ
Nganga
Joseph
J
Moran-Giuati
Angela
A
Szafranek
Timothy R
TR
Johnson
Ashley J
AJ
Bigelow
Christiane M
CM
Houde
Herve
H
Avet-Loiseau
Dominic J
DJ
Smiraglia
Noreen
N
Ersing
Asher A
AA
Chanan-Khan
Lionel J
LJ
Coignet
D001692:Biological Transport; D045744:Cell Line, Tumor; D017931:DNA Primers; D018076:DNA, Complementary / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D000072101:Jagged-2 Protein; D008565:Membrane Proteins / Q000235:genetics*; D009101:Multiple Myeloma / Q000235:genetics*; D056985:Nuclear Receptor Co-Repressor 2; D011401:Promoter Regions, Genetic; D011994:Recombinant Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000099186:Histone Deacetylase 3
D017931:DNA Primers; D018076:DNA, Complementary; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D006655:Histone Deacetylases; D036341:Intercellular Signaling Peptides and Proteins; D000072101:Jagged-2 Protein; D008565:Membrane Proteins; D056985:Nuclear Receptor Co-Repressor 2; D011994:Recombinant Proteins; D012097:Repressor Proteins; D000099186:Histone Deacetylase 3; C490504:JAG2 protein, human; C539130:NCOR2 protein, human