Epigenetic regulation of cell adhesion-mediated drug resistance acquisition in multiple myeloma.
Elucidation of the epigenetic mechanisms underlying drug resistance may greatly contribute to the advancement of cancer therapies. In the present study, we identified trimethylation of histone H3 at lysine-27 (H3K27me3) as a critical histone modification for cell adhesion-mediated drug resistance (CAM-DR), which is the most important form of drug resistance in multiple myeloma. Cell adhesion counteracted drug-induced hypermethylation of H3K27 via inactivating phosphorylation of EZH2, leading to sustained expression of anti-apoptotic genes including IGF1, BCL2 and HIF1A. Inhibition of the IGF-1R/PI3K/Akt pathway reversed CAM-DR by promoting EZH2 dephosphorylation and H3K27 hypermethylation both in vitro and in refractory murine myeloma models. To our knowledge, this is the first demonstration of an epigenetic mechanism underlying CAM-DR and provides a rationale for the inclusion of kinase inhibitors counteracting EZH2 phosphorylation in combination chemotherapy aimed at increasing the therapeutic index.
Division of Stem Cell Regulation, Center for Molecular Medicine, Jichi Medical University.
Yusuke
Y
Furukawa
Jiro
J
Kikuchi
D000818:Animals; D002448:Cell Adhesion; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009101:Multiple Myeloma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D015398:Signal Transduction