The potential role of epigenetic therapy in multiple myeloma.
This review describes the role that epigenetic changes play in the pathogenesis of cancer, concentrating on the plasma cell malignancy multiple myeloma, and highlights recent findings regarding the efficacy of epigenetic therapeutic agents in laboratory studies and clinical trials. DNA methylation is altered in a wide range of cancers with hypermethylation of CpG islands associated with silencing of tumour suppressor genes. Genes found to be silenced by methylation in myeloma samples include VHL, TP53, CDKN2A, and TGFBR2. Myeloma is linked to the overexpression of a histone methylatransferase (MMSET) and inactivating mutations of a histone demethylase (UTX), suggesting that the regulation of histone methylation is a potential therapeutic target. Abnormal expression of histone deacetylases (HDACs) has been widely described in solid tumours and haematological malignancies. In myeloma, histone deacetylase inhibitors show promising results both in laboratory-based cell culture studies and in clinical trials, where they demonstrate particularly good therapeutic outcome when administered in combination with other standard chemotherapeutic agents. The study of epigenetics shows great promise for understanding the alterations in gene expression that underlie malignancies and provides exciting novel drugable targets.
Smith
Emma M
EM
Institute of Cancer Research, Sutton, Surrey, UK.
Boyd
Kevin
K
Davies
Faith E
FE
D018899:CpG Islands / Q000187:drug effects*; D019175:DNA Methylation / Q000187:drug effects*; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D044127:Epigenesis, Genetic; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use*; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics
D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D015254:DNA Modification Methylases; D006655:Histone Deacetylases