HDAC5 is required for maintenance of pericentric heterochromatin, and controls cell-cycle progression and survival of human cancer cells
HDAC5 is required for maintenance of pericentric heterochromatin, and controls cell-cycle progression and survival of human cancer cells
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DOI：
10.1038/cdd.2012.3
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发表时间：
2012-07-01
影响因子：
12.4
通讯作者：
Mottet, D.
中科院分区：
文献类型：
--
作者：
Peixoto, P.;Castronovo, V.;Mottet, D.
组蛋白脱乙酰酶（HDAC）形成一个酶家族，在基因表达的表观遗传调节中发挥重要作用，并有助于癌细胞的生长、分化和凋亡。在这项研究中，我们进一步研究了HDAC 5在癌细胞中的生物学功能。我们发现HDAC 5与S期晚期臂间异染色质的活跃复制有关。我们证明了通过RNA干扰特异性地消耗HDAC 5导致异染色质结构的深刻变化，并减缓了正在进行的复制叉。这种异染色质维持和组装的缺陷通过DNA损伤检查点途径感知，其触发癌细胞自噬和凋亡，并在体外和体内抑制其生长。最后，我们还证明了HDAC 5耗竭导致DNA对DNA损伤剂的敏感性增强，这表明由组蛋白HDAC 5沉默诱导的异染色质去缩合可以增强通过体外靶向DNA起作用的细胞毒性剂的功效。总之，这些结果首次强调了HDAC 5与异染色质结构的维持/组装之间未被认识到的联系，并证明其特异性抑制可能有助于提高基于DNA改变的癌症治疗在临床上的疗效。Cell Death and Differentiation（2012）19，1239-1252; doi：10.1038/cdd.2012.3; 2012年2月3日在线发表
Histone deacetylases (HDACs) form a family of enzymes, which have fundamental roles in the epigenetic regulation of gene expression and contribute to the growth, differentiation, and apoptosis of cancer cells. In this study, we further investigated the biological function of HDAC5 in cancer cells. We found HDAC5 is associated with actively replicating pericentric heterochromatin during late S phase. We demonstrated that specific depletion of HDAC5 by RNA interference resulted in profound changes in the heterochromatin structure and slowed down ongoing replication forks. This defect in heterochromatin maintenance and assembly are sensed by DNA damage checkpoint pathways, which triggered cancer cells to autophagy and apoptosis, and arrested their growth both in vitro and in vivo. Finally, we also demonstrated that HDAC5 depletion led to enhanced sensitivity of DNA to DNA-damaging agents, suggesting that heterochromatin de-condensation induced by histone HDAC5 silencing may enhance the efficacy of cytotoxic agents that act by targeting DNA in vitro. Together, these results highlighted for the first time an unrecognized link between HDAC5 and the maintenance/assembly of heterochromatin structure, and demonstrated that its specific inhibition might contribute to increase the efficacy of DNA alteration-based cancer therapies in clinic. Cell Death and Differentiation (2012) 19, 1239-1252; doi: 10.1038/cdd.2012.3; published online 3 February 2012