Liu Hongbin, Pattie Phillip, Chandrasekara Sahan, Spencer Andrew, Dear Anthony E
Australian Centre for Blood Diseases, Monash University, Melbourne, Victoria 3004, Australia; Translational Research Division, Eastern Clinical Research Unit, Australian Centre for Blood Diseases, Monash University, Melbourne, Victoria 3004, Australia.
Department of Medicine, Eastern Health Clinical School, Monash University, Melbourne, Victoria 3128, Australia.
Oncol Lett. 2016 Sep;12(3):2175-2180. doi: 10.3892/ol.2016.4912. Epub 2016 Jul 25.
Epigenetic regulation of microRNA (miRNA) expression has recently been implicated in the pathogenesis of myelodysplastic syndrome (MDS). Particular interest has focused on miRNA-124 expression, which is inhibited in MDS and has recently been demonstrated to be upregulated in response to epigenetic treatment (EGT). Previous studies have determined the and expression of miRNA-124 and several molecular targets, including cyclin-dependent kinase (CDK) 4, CDK6 and enhancer of zeste homolog 2 (EZH2), in order to elucidate the molecular mechanisms associated with the miRNA-124-mediated therapeutic response to EGT in MDS and identify additional potential biomarkers of early EGT treatment response in myeloid malignancies. studies in the HL60 leukemic cell line identified upregulation of miRNA-124 expression in response to single-agent EGT with either azacytidine (AZA) or the histone deacetylase inhibitor panobinostat (LBH589). Combination EGT with AZA and LBH589 resulted in significant additive induction of miRNA-124 expression. Expression of downstream targets of miRNA-124, including CDK4, CDK6 and EZH2, in response to single agent and combined EGT was determined in HL60 cells. Single and combination EGT treatment resulted in inhibition of CDK4, CDK6 and EZH2 expression with combination EGT resulting in a significant and additive inhibitory effect. studies using peripheral blood mononuclear cells from patients receiving combination EGT for high risk MDS or acute myeloid leukemia demonstrated significant induction of miRNA-124 and inhibition CDK4 and CDK6 messenger (m)RNA expression in patients that responded to combination EGT. A trend to inhibited EZH2 mRNA expression was also identified in response to combination EGT. Overall, the present observations identify a potential molecular mechanism for miRNA-124-mediated response to EGT involving regulation of CDK4, CDK6 and EZH2 expression. In addition, the present findings further qualify miRNA-124 as a possible biomarker of early response to EGT in myeloid malignancies and potentially a valid therapeutic target, together with CDK4, CDK6 and EZH2.
微小RNA（miRNA）表达的表观遗传调控最近被认为与骨髓增生异常综合征（MDS）的发病机制有关。特别受到关注的是miRNA-124的表达，它在MDS中受到抑制，最近已证明其在表观遗传治疗（EGT）后会上调。先前的研究已经确定了miRNA-124的表达以及几个分子靶点，包括细胞周期蛋白依赖性激酶（CDK）4、CDK6和zeste同源物2增强子（EZH2），以阐明与miRNA-124介导的MDS对EGT治疗反应相关的分子机制，并确定髓系恶性肿瘤中EGT早期治疗反应的其他潜在生物标志物。在HL60白血病细胞系中的研究发现，用阿扎胞苷（AZA）或组蛋白去乙酰化酶抑制剂帕比司他（LBH589）进行单药EGT可使miRNA-124表达上调。AZA和LBH589联合EGT可显著增强miRNA-124的诱导表达。在HL60细胞中测定了miRNA-124下游靶点（包括CDK4、CDK6和EZH2）对单药和联合EGT的反应。单药和联合EGT治疗均导致CDK4、CDK6和EZH2表达受到抑制，联合EGT具有显著的叠加抑制作用。对接受联合EGT治疗高危MDS或急性髓系白血病患者的外周血单个核细胞进行的研究表明，对联合EGT有反应的患者中miRNA-124显著诱导，CDK4和CDK6信使核糖核酸（mRNA）表达受到抑制。联合EGT后还发现EZH2 mRNA表达有受抑制的趋势。总体而言，目前的观察结果确定了miRNA-124介导的对EGT反应的潜在分子机制，涉及CDK4、CDK6和EZH2表达的调控。此外，目前的研究结果进一步证明miRNA-124可能是髓系恶性肿瘤中EGT早期反应的生物标志物，并且与CDK4、CDK6和EZH2一起可能是有效的治疗靶点。
