The human HECA interacts with cyclins and CDKs to antagonize Wnt-mediated proliferation and chemoresistance of head and neck cancer cells
The human HECA interacts with cyclins and CDKs to antagonize Wnt-mediated proliferation and chemoresistance of head and neck cancer cells
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DOI：
10.1016/j.yexcr.2011.11.004
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发表时间：
2012-03-10
影响因子：
3.7
通讯作者：
Reichert, Torsten E.
中科院分区：
文献类型：
--
作者：
Dowejko, Albert;Bauer, Richard;Reichert, Torsten E.
越来越多的证据表明，果蝇头壳的人类同源物(HECA)在人类癌症发生中发挥着重要作用。到目前为止，HECA的特定蛋白相互作用伙伴和受影响的信号通路仍然是未知的。在最近的一项研究中，我们发现HECA在口腔鳞状细胞癌角质形成细胞中的过表达具有肿瘤抑制作用，导致细胞周期控制的恢复，涉及S期、G2期和M期的进入和进展。目前，定量RT-PCR和免疫组织化学分析表明，口腔鳞癌患者原发肿瘤组织中HECA的表达明显低于正常对照组，HECA表达丰富。此外，口腔鳞癌转移灶中几乎没有HECA的表达。在这里，我们发现HECA的表达受到Wnt途径的负调控，并且Wnt相关的转录因子TCF4与HECA启动子结合。此外，免疫细胞化学显示HECA与细胞周期蛋白依赖性激酶CDK9共定位。免疫沉淀实验和邻近连接实验进一步揭示了HECA与CDK2、CDK9、Cyclin A和Cyclin K的相互作用，Cyclin K是P53抑癌基因的直接转录靶点。沉默口腔鳞癌细胞系中的HECA可显著增加细胞分裂，并显著增加对化疗药物顺铂的耐药性。相反，过表达HECA的口腔鳞癌细胞株对顺铂的耐受性降低。因此，HECA可能被认为是未来治疗Wnt依赖肿瘤进展的药物。(C)2011 Elsevier Inc.保留所有权利。
There is a growing evidence that the human homologue of the Drosophila headcase (HECA) plays an important role in human carcinogenesis. So far specific protein interaction partners and affected signaling pathways of HECA are still elusive. In a recent study we showed that HECA overexpression in oral squamous-cell carcinoma (OSCC) keratinocytes has tumor suppressive effects resulting in a recuperation of cell cycle control concerning the entry and progression of S-phase, G2- and M-phase. Currently, quantitative RT-PCR and immunohistochemical analysis of primary tumor tissue from OSCC patients demonstrate that HECA expression is markedly decreased compared to normal control patients with abundant HECA expression. Additionally, there is nearly no HECA expression in OSCC metastases. Here, we show that HECA expression is negatively controlled by the Wnt-pathway and TCF4, a Wnt related transcription factor, binds to the HECA promoter. Furthermore, immunocytochemistry reveals colocalization of HECA with the cyclin dependent kinase CDK9. Immunoprecipitation experiments and proximity ligation assays further reveal an interaction of HECA with CDK2, CDK9, Cyclin A and Cyclin K, a direct transcriptional target of the p53 tumor suppressor. Silencing HECA in OSCC cell lines leads to a significant increase of cell division and a markedly increased resistance against the chemotherapeutic cisplatin. On the contrary, HECA overexpressing OSCC cell lines show decreased resistance of OSCC cells against cisplatin. Therefore, HECA could be considered as future therapeutic agent against Wnt-dependent tumor progression. (C) 2011 Elsevier Inc. All rights reserved.