Histone deacetyllase inhibitor suberoylanilide hydroxamic acid induces apoptosis through both mitochondriall and Fas (Cd95) signalling in head and neck squamous carcinorna cells
Histone deacetyllase inhibitor suberoylanilide hydroxamic acid induces apoptosis through both mitochondriall and Fas (Cd95) signalling in head and neck squamous carcinorna cells
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DOI：
10.1158/1535-7163.mct-04-0344
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发表时间：
2007-11-01
影响因子：
5.7
通讯作者：
Lotan, Reuben
中科院分区：
文献类型：
--
作者：
Gillenwater, Ann M.;Zhong, Meiling;Lotan, Reuben
组蛋白乙酰化状态的改变与癌发生有关。组蛋白去乙酰化酶抑制剂，如辛二酰苯胺异羟肟酸（SAHA），可以通过恢复组蛋白乙酰化和允许基因转录来潜在地重新激活异常沉默的基因。然而，SAHA对细胞生长、分化和死亡的影响的潜在机制仍不清楚。在这项研究中，我们评估的活动，SAHA在调节细胞生长和凋亡，在头颈部鳞状细胞癌（HNSCC）线圈相比，癌前白斑和正常的口腔细胞。SAHA诱导HNSCC细胞系生长抑制、细胞周期改变和凋亡，但对癌前病变和正常细胞的作用有限。虽然SAHA触发了线粒体途径的细胞凋亡，包括细胞色素c的释放，caspase-3和caspase-9的激活，和聚（ADP-核糖）聚合酶裂解在HNSCC细胞，特异性抑制caspase-9只部分阻断诱导凋亡的诱导。SAHA还激活了外源性凋亡途径，包括增加Fas和Fas配体（FasL）表达，激活caspase-8和Bid裂解。Fas信号的干扰阻断凋亡诱导和钝化生长抑制SAHA。我们的研究结果表明，第一次，SAHA诱导凋亡HNSCC细胞通过激活Fas/FasL死亡途径，除了固有的线粒体途径，虽然有相对较小的活性对癌前病变和正常的口腔细胞与内在的Fas和FasL表达。[Mol Cancer Ther 2007;6（11）：2967-75]。
Alterations in histone acetylation :status have been implicated in carcinogenesis. Histone deacetylase inhibitors, such as suberoylanilide hydroxamic acid (SAHA), can potentially reactivate aberrantly silenced genes by restoring histone acetylation and allowing gene transcription. However, the mechanisms underlying the effects of SAHA on cell growth, differentiation, and death remain unclear. In this study, we assessed the activity of SAHA in modulating cell growth and apoptosis, in head and neck squamous cell carcinoma (HNSCC) coils compared with premalignant leukoplakia and normal oral cells. SAHA induced growth inhibition, cell cycle changes, and apoptosis in HNSCC cell lines but had limited effects on premalignant and normal cells. Although SAHA triggered the mitochondrial pathway of apoptosis, including cytochrome c release, caspase-3 and caspase-9 activation, and poly(ADP-ribose) polymerase cleavage in HNSCC cells, specific inhibition of caspase-9 only partially blocked the induction of apoptosis induction. SAHA also activated the extrinsic apoptosis pathway, including increased Fas and Fas ligand (FasL) expression, activation of caspase-8, and cleavage of Bid. Interfering with Fas signaling blocked apoptosis induction and blunted growth inhibition by SAHA. Our results show for the first time that SAHA induces apoptosis in HNSCC cells through activation of the Fas/FasL death pathway in addition to the intrinsic mitochondrial pathway although having comparatively little activity against precancerous and normal oral cells with intrinsic Fas and FasL expression. [Mol Cancer Ther 2007;6(11):2967-75].