Loss of the SMRT/NCoR2 Corepressor Correlates with JAG2 Overexpression in Multiple Myeloma

Abstract

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.

Notch pathway inhibition controls myeloma bone disease in the murine MOPC315.BM model

“…Overexpression of Jagged2 can be triggered either by promoter hypomethylation, 12 through aberrant expression of the ubiquitin ligase Skeletrophin 13 or by loss of SMRT/NCoR2 corepressor, which results in abnormal acetylation of the Jagged2 promoter. 14 In MM, Notch confers resistance to apoptotic stimuli and protects against chemotherapy-induced toxicity. 15, 16 Nefedova et al 15 described that Notch signalling is involved in de novo drug resistance triggered by bone marrow stroma.…”

Combined effects of FLT3 and NF‐κB selective inhibitors on acute myeloid leukemia in vivo

“…It indicates that downregulating cyclin D1 by SC-203048 or PTL may be a factor contributing to the tumor growth inhibition. SMRT is one of the most common transcriptional repression factors and plays an important role in several cancers [27][28][29]. Our previous study showed that decreased expression of SMRT existed in THP-1 cell line, and it is an important downstream molecule of FLT3/p65 signaling pathway [30].…”

Glycosylation Inhibitors Efficiently Inhibit P-Selectin-Mediated Cell Adhesion to Endothelial Cells

“…Western blotting was performed as previously described [27]. Briefly, protein lysates were prepared by incubating cells with a lysis buffer as described [27].…”

“…Briefly, protein lysates were prepared by incubating cells with a lysis buffer as described [27]. Cell debris was removed by centrifugation (14,000×g, 15 min at 4°C).…”

“…One milligram of total cell lysates was immunoprecipitated using P-selectin antibody (H-150) and protein A agarose beads as described [27]. Proteins immobilized on agarose beads were eluted with 0.1 M glycine buffer (pH 2.8).…”