Comparison of Expression Signature of Histone Deacetylases (HDACs) in Mesenchymal Stem Cells from Multiple Myeloma and Normal Donors

  • Ahmadvand, Mohammad (Department of Hematology, Faculty of Medical Sciences, Tarbiat Modares University) ;
  • Noruzinia, Mehrdad (Department of Medical Genetics, School of Medicine, Tarbiat Modares University) ;
  • Soleimani, Masoud (Department of Hematology, Faculty of Medical Sciences, Tarbiat Modares University) ;
  • Abroun, Saeid (Department of Hematology, Faculty of Medical Sciences, Tarbiat Modares University)
  • Published : 2016.07.01


Background: Histone acetylation in chromatin structures plays a key role in regulation of gene transcription and is strictly controlled by histone acetyltransferase (HAT) and deacetylase (HDAC) activities. HDAC deregulation has been reported in several cancers. Materials and Methods: The expression of 10 HDACs (including HDAC class I and II) was studied by quantitative reverse transcription-PCR (qRT-PCR) in a cohort of mesenchymal stem cells (MM-MSCs) from 10 multiple myeloma patients with a median age 60y. The results were compared with those obtained for normal donors. Then, a coculture system was performed between MM-MSCs and u266 cell line, in the presence or absence of sodium butyrate (NaBT), to understand the effects of HDAC inhibitors (HDACi) in MM-MSCs on multiple myeloma cases. Also, the interleukin-6 (IL-6) and vascular endothelial growth factor (VEGFA) gene expression level and apoptotic effects were investigated in MM-MSCs patients and control group following NaBT treatment. Results: The results indicated that upregulated (HDACs) and downregulated (IL6 and VEGFA) genes were differentially expressed in the MM-MSCs derived from patients with multiple myeloma and ND-MSCs from normal donors. Comparison of the MM-MSCs and ND-MSCs also showed distinct HDACs expression patterns. For the first time to our knowledge, a significant increase of apoptosis was observed in coculture with MM-MSCs treated with NaBT. Conclusions: The obtained findings elucidate a complex set of actions in MSCs in response to HDAC inhibitors, which may be responsible for anticancer effects. Also, the data support the idea that MSCs are new therapeutic targets as a potential effective strategy for MM.


Multiple myeloma;histone deacetylase;mesenchymal stem cell;interleukin-6


  1. Ashraf N, Zino S, Macintyre A, et al (2006). Altered sirtuin expression is associated with node-positive breast cancer. Br J Cancer, 95, 1056-61.
  2. Bartl S, Taplick J, Lagger G, et al (1997). Identification of mouse histone deacetylase 1 as a growth factor-inducible gene. Molecular Cellular Biol, 17, 5033-43.
  3. Bergfeld SA, DeClerck YA (2010). Bone marrow-derived mesenchymal stem cells and the tumor microenvironment. Cancer Metastasis Reviews, 29, 249-61.
  4. Catley L, Weisberg E, Tai YT, et al (2003). NVP-LAQ824 is a potent novel histone deacetylase inhibitor with significant activity against multiple myeloma. Blood, 102, 2615-22.
  5. De Becker A, Van Hummelen P, Bakkus M, et al (2007). Migration of culture-expanded human mesenchymal stem cells through bone marrow endothelium is regulated by matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-3. Haematologica, 92, 440-9.
  6. Fandy TE, Shankar S, Ross DD, et al (2005). Interactive effects of HDAC inhibitors and TRAIL on apoptosis are associated with changes in mitochondrial functions and expressions of cell cycle regulatory genes in multiple myeloma. Neoplasia, 7, 646-57.
  7. Forsberg EC, Bresnick EH (2001). Histone acetylation beyond promoters: long-range acetylation patterns in the chromatin world*. Bioessays, 23, 820-30.
  8. Goldstein RH, Reagan MR, Anderson K, et al (2010). Human bone marrow-derived MSCs can home to orthotopic breast cancer tumors and promote bone metastasis. Cancer Res, 70, 10044-50.
  9. Gray SG, Ekstrom TJ (1998). Effects of cell density and trichostatin A on the Expression of HDAC1and p57Kip2in Hep 3B Cells. Biochemical Biophysical Res Communications, 245, 423-7.
  10. Halkidou K, Gaughan L, Cook S, et al (2004). Upregulation and nuclear recruitment of HDAC1 in hormone refractory prostate cancer. Prostate, 59, 177-89.
  11. Kaiser M, Zavrski I, Sterz J, et al (2006). The effects of the histone deacetylase inhibitor valproic acid on cell cycle, growth suppression and apoptosis in multiple myeloma. Haematologica, 91, 248-51.
  12. Klein B, Bataille R (1992). Cytokine network in human multiple myeloma. Hematol/Oncol Clinics North America, 6, 273-84.
  13. Kyle RA, Gertz MA, Witzig TE, et al (2003). Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clinic Proceedings, 2003. Elsevier, 21-33.
  14. Lauta VM (2001). Interleukin-6 and the network of several cytokines in multiple myeloma: an overview of clinical and experimental data. Cytokine, 16, 79-86.
  15. Lemaire M, Deleu S, De Bruyne E, et al (2011). The microenvironment and molecular biology of the multiple myeloma tumor. Advances Cancer Res, 110, 20.
  16. Lin RJ, Sternsdorf T, Tini M, et al (2001). Transcriptional regulation in acute promyelocytic leukemia. Oncogene, 20, 7204-15.
  17. Lu Q, Lin X, Feng J, et al (2008). Phenylhexyl isothiocyanate has dual function as histone deacetylase inhibitor and hypomethylating agent and can inhibit myeloma cell growth by targeting critical pathways. J Hematol Oncol, 9, 1-6.
  18. Minucci S, Pelicci PG (2006). Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nature Reviews Cancer, 6, 38-51.
  19. Mitsiades N, Mitsiades CS, Richardson PG, et al (2003). Molecular sequelae of histone deacetylase inhibition in human malignant B cells. Blood, 101, 4055-62.
  20. Nishimoto N, Kishimoto T (2006). Interleukin 6: from bench to bedside. Nature Clin Practice Rheumatol, 2, 619-26.
  21. Park JK, Cho CH, Ramachandran S, et al (2006). Augmentation of sodium butyrate-induced apoptosis by phosphatidylinositol 3-kinase inhibition in the human cervical cancer cell-line. Cancer Res Treatment, 38, 112-7.
  22. Reagan MR, Ghobrial IM (2012). Multiple myeloma mesenchymal stem cells: characterization, origin, and tumor-promoting effects. Clinical Cancer Res, 18, 342-9.
  23. Secrist J, Zhou X, Richon V (2003). HDAC inhibitors for the treatment of cancer. Current opinion in investigational drugs (London, England: 2000), 4, 1422-7.
  24. Skov V, Larsen TS, Thomassen M, et al (2012). Increased gene expression of histone deacetylases in patients with Philadelphia-negative chronic myeloproliferative neoplasms. Leukemia Lymphoma, 53, 123-9.
  25. Smith EM, Boyd K, Davies FE (2010). The potential role of epigenetic therapy in multiple myeloma. British J Haematol, 148, 702-13.
  26. Todoerti K, Lisignoli G, Storti P, et al (2010). Distinct transcriptional profiles characterize bone microenvironment mesenchymal cells rather than osteoblasts in relationship with multiple myeloma bone disease. Experimental hematology, 38, 141-53.
  27. Van Damme M, Crompot E, Meuleman N, et al (2012). HDAC isoenzyme expression is deregulated in chronic lymphocytic leukemia B-cells and has a complex prognostic significance. Epigenetics, 7, 1403-12.
  28. Verdel A, Khochbin S (1999). Identification of a new family of higher eukaryotic histone deacetylases coordinate expression of differentiation-dependent chromatin modifiers. J Biological Chemistry, 274, 2440-5.
  29. Wang J, Hoshino T, Redner RL, et al (1998). ETO, fusion partner in t (8; 21) acute myeloid leukemia, represses transcription by interaction with the human N-CoR/mSin3/HDAC1 complex. Proceedings National Academy Sciences, 95, 10860-5.
  30. Weichert W (2009). HDAC expression and clinical prognosis in human malignancies. Cancer Letters, 280, 168-76.
  31. Workman J, Kingston R (1998). Alteration of nucleosome structure as a mechanism of transcriptional regulation. Annual Review Biochemistry, 67, 545-79.
  32. Xu S, De Veirman K, Evans H, et al (2013). Effect of the HDAC inhibitor vorinostat on the osteogenic differentiation of mesenchymal stem cells in vitro and bone formation in vivo. Acta Pharmacologica Sinica, 34, 699-709.
  33. Zhang Z, Yamashita H, Toyama T, et al (2004). HDAC6 expression is correlated with better survival in breast cancer.