Aberrant regulation of HDAC2 mediates proliferation of hepatocellular carcinoma cells by deregulating expression of G1/S cell cycle proteins.
Aberrant regulation of HDAC2 mediates proliferation of hepatocellular carcinoma cells by deregulating expression of G1/S cell cycle proteins.
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DOI：
10.1371/journal.pone.0028103
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Nam SW
中科院分区：
文献类型：
--
作者：
Noh JH;Jung KH;Kim JK;Eun JW;Bae HJ;Xie HJ;Chang YG;Kim MG;Park WS;Lee JY;Nam SW
组蛋白去乙酰化酶2（HDAC 2）对胚胎发育至关重要，影响与免疫应答相关的细胞因子信号传导，并且通常在实体瘤中显著过表达;但对其在人肝细胞癌（HCC）中的作用知之甚少。在这项研究中，我们发现HDAC 2的靶向破坏导致Hep 3B细胞中肿瘤细胞生长和从头DNA合成的减少。然后，我们证明了HDAC 2调节细胞周期，并且HDAC 2的破坏导致细胞周期中的G1/S停滞。在G1/S转换期，HDAC 2的靶向阻断选择性地诱导p16 INK 4A和p21 WAF 1/Cip 1的表达，同时抑制cyclin D1、CDK 4和CDK 2的表达。因此，HDAC 2抑制通过降低pRb蛋白的磷酸化状态导致E2 F/DP 1靶基因的下调。此外，HDAC 2的持续抑制减弱了小鼠异种移植模型中的体外集落形成和体内肿瘤生长。进一步的，我们发现HDAC 2通过p21 WAF 1/Cip 1启动子近端富集的Sp1结合位点抑制p21 WAF 1/Cip 1的转录活性。总之，我们认为HDAC 2的异常调节可能通过其在转录水平上调节细胞周期组分在HCC的发展中发挥关键作用，从而提供HDAC 2作为肝癌治疗的相关靶点。
Histone deacetylase 2 (HDAC2) is crucial for embryonic development, affects cytokine signaling relevant for immune responses and is often significantly overexpressed in solid tumors; but little is known about its role in human hepatocellular carcinoma (HCC). In this study, we showed that targeted-disruption of HDAC2 resulted in reduction of both tumor cell growth and de novo DNA synthesis in Hep3B cells. We then demonstrated that HDAC2 regulated cell cycle and that disruption of HDAC2 caused G1/S arrest in cell cycle. In G1/S transition, targeted-disruption of HDAC2 selectively induced the expression of p16INK4A and p21WAF1/Cip1, and simultaneously suppressed the expression of cyclin D1, CDK4 and CDK2. Consequently, HDAC2 inhibition led to the down-regulation of E2F/DP1 target genes through a reduction in phosphorylation status of pRb protein. In addition, sustained suppression of HDAC2 attenuated in vitro colony formation and in vivo tumor growth in a mouse xenograft model. Further, we found that HDAC2 suppresses p21WAF1/Cip1 transcriptional activity via Sp1-binding site enriched proximal region of p21WAF1/Cip1 promoter. In conclusion, we suggest that the aberrant regulation of HDAC2 may play a pivotal role in the development of HCC through its regulation of cell cycle components at the transcription level providing HDAC2 as a relevant target in liver cancer therapy.
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影响因子：
29.4
作者：
Laurent-Puig, P;Legoix, P;Zucman-Rossi, J
通讯作者：
Zucman-Rossi, J
影响因子：
13.5
作者：
Nam, SW;Park, JY;Lee, JY
通讯作者：
Lee, JY
影响因子：
64.5
作者：
Laherty, CD;Yang, WM;Eisenman, RN
通讯作者：
Eisenman, RN
影响因子：
3.7
作者：
Kaler, Pawan;Sasazuki, Takehiko;Klampfer, Lidija
通讯作者：
Klampfer, Lidija
组蛋白脱乙酰基酶1、2和3在前列腺癌中高度表达，而HDAC2表达与前列腺癌后psa的PSA复发时间较短有关。
影响因子：
8.8
作者：
Weichert, W.;Roeske, A.;Gekeler, V.;Beckers, T.;Stephan, C.;Jung, K.;Fritzsche, F. R.;Niesporek, S.;Denkert, C.;Dietel, M.;Kristiansen, G.
通讯作者：
Kristiansen, G.