Epigenetic modification of gene expression by interference with histone acetylation.

Different studies indicate that the expression of various genes regulating differentiation, proliferation and apoptosis are partly controlled by changes in histone status, regulated in turn through acetylation and deacetylatio. In both heamatological and non-heamatological malignancies, aberrant histone acetylation/deacetylation is involved in processes such as growth arrest, differentiation and apoptosis.
Recent studies have demonstrated the sensibility of human myeloma cell lines to suberoylanilide hydroxamic acid (SAHA), depsipeptide (FR901228) and NVP-LAQ824, inducing apoptosis of MM cell lines in a time and concentration dependent fashion. The molecular sequela of the HDAC inhibition in MM cells also seem pleiotropic, including downregulation of transcripts,of IGF-1/IGF-1R, Il-6 R signaling cascades, anti-apoptotic molecules, oncogenic kinases, DNA synthesis/repair enzymes and transcription factors, offering the advantage of targeting different proliferative /antiapoptotic pathways in the tumor cells. SAHA also enhances the anti-myeloma activity of other proapoptotic agents including dexamethasone, cytotoxic chemotherapy and thalidomide analogs.
The aim of this part of the GOA project is to investigate epigenetic alteractions within candidate gene in MM, look at biological effects of broad spectrum inhibitors at different levels of development of the myeloma disease and to identify which HDAC are key players in MM disease.