Loss of the SMRT/NCoR2 corepressor correlates with JAG2 overexpression in multiple myeloma

Pushpankur Ghoshal, Alain J. Nganga, Joseph Moran-Giuati, Angela Szafranek, Timothy R. Johnson, Ashley J. Bigelow, Christiane M. Houde, Herve Avet-Loiseau, Dominic J. Smiraglia, Noreen Ersing, Asher A. Chanan-Khan, Lionel J. Coignet

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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.

Original languageEnglish (US)
Pages (from-to)4380-4387
Number of pages8
JournalCancer Research
Volume69
Issue number10
DOIs
StatePublished - May 15 2009

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Nuclear Receptor Co-Repressor 2
Multiple Myeloma
Genetic Promoter Regions
Histone Deacetylases
Acetylation
Plasma Cells
Cell Line
Interleukin-6
B-Lymphocytes
Cytokines
Co-Repressor Proteins
Hematologic Neoplasms
Epigenomics
Histones
Genes
Down-Regulation

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Ghoshal, P., Nganga, A. J., Moran-Giuati, J., Szafranek, A., Johnson, T. R., Bigelow, A. J., ... Coignet, L. J. (2009). Loss of the SMRT/NCoR2 corepressor correlates with JAG2 overexpression in multiple myeloma. Cancer Research, 69(10), 4380-4387. https://doi.org/10.1158/0008-5472.CAN-08-3467

Loss of the SMRT/NCoR2 corepressor correlates with JAG2 overexpression in multiple myeloma. / Ghoshal, Pushpankur; Nganga, Alain J.; Moran-Giuati, Joseph; Szafranek, Angela; Johnson, Timothy R.; Bigelow, Ashley J.; Houde, Christiane M.; Avet-Loiseau, Herve; Smiraglia, Dominic J.; Ersing, Noreen; Chanan-Khan, Asher A.; Coignet, Lionel J.

In: Cancer Research, Vol. 69, No. 10, 15.05.2009, p. 4380-4387.

Research output: Contribution to journalArticle

Ghoshal, P, Nganga, AJ, Moran-Giuati, J, Szafranek, A, Johnson, TR, Bigelow, AJ, Houde, CM, Avet-Loiseau, H, Smiraglia, DJ, Ersing, N, Chanan-Khan, AA & Coignet, LJ 2009, 'Loss of the SMRT/NCoR2 corepressor correlates with JAG2 overexpression in multiple myeloma', Cancer Research, vol. 69, no. 10, pp. 4380-4387. https://doi.org/10.1158/0008-5472.CAN-08-3467
Ghoshal P, Nganga AJ, Moran-Giuati J, Szafranek A, Johnson TR, Bigelow AJ et al. Loss of the SMRT/NCoR2 corepressor correlates with JAG2 overexpression in multiple myeloma. Cancer Research. 2009 May 15;69(10):4380-4387. https://doi.org/10.1158/0008-5472.CAN-08-3467
Ghoshal, Pushpankur ; Nganga, Alain J. ; Moran-Giuati, Joseph ; Szafranek, Angela ; Johnson, Timothy R. ; Bigelow, Ashley J. ; Houde, Christiane M. ; Avet-Loiseau, Herve ; Smiraglia, Dominic J. ; Ersing, Noreen ; Chanan-Khan, Asher A. ; Coignet, Lionel J. / Loss of the SMRT/NCoR2 corepressor correlates with JAG2 overexpression in multiple myeloma. In: Cancer Research. 2009 ; Vol. 69, No. 10. pp. 4380-4387.
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