Histone Lysine Methyltransferase Wolf-Hirschhorn Syndrome Candidate 1 Is Involved in Human Carcinogenesis through Regulation of the Wnt Pathway
Histone Lysine Methyltransferase Wolf-Hirschhorn Syndrome Candidate 1 Is Involved in Human Carcinogenesis through Regulation of the Wnt Pathway
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DOI：
10.1593/neo.11048
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发表时间：
2011-10-01
期刊：
影响因子：
4.8
通讯作者：
Hamamoto, Ryuji
中科院分区：
文献类型：
--
作者：
Toyokawa, Gouji;Cho, Hyun-Soo;Hamamoto, Ryuji
许多组蛋白甲基转移酶已被鉴定并具有生化特征，但其功能障碍在癌症等人类疾病中的病理作用尚不清楚。在这里，我们证明了沃尔夫-赫希霍恩综合征候选基因1(WHSC1)在人类癌症发生中起着重要作用。该基因的转录水平在包括膀胱癌和肺癌在内的各种癌症中显著升高。对一些临床组织的免疫组织化学分析证实，WHSC1在蛋白水平上显著上调了膀胱癌和肺癌细胞的表达。以WHSC1为靶点的小干扰RNA可显著下调WHSC1的表达，并抑制其增殖。流式细胞仪细胞周期分析显示，WHSC1基因敲除后，S期癌细胞数量减少，而G(2)/M期细胞数量增加。WHSC1与包括β-连环素在内的一些与WNT途径相关的蛋白质相互作用，并通过组蛋白H3在36位赖氨酸的三甲基化来转录调节β-连环素/Tcf-4复合体的靶基因CCND1。这是通过组蛋白H3的表观遗传调控，在人类癌变过程中WNT途径失控的一种新机制。由于WHSC1在大多数正常组织类型中的表达水平明显较低，因此开发针对该酶的特异性和选择性抑制剂作为具有最小不良反应风险的抗肿瘤药物应该是可行的。
A number of histone methyltransferases have been identified and biochemically characterized, but the pathologic roles of their dysfunction in human diseases like cancer are not well understood. Here, we demonstrate that Wolf-Hirschhorn syndrome candidate 1 (WHSC1) plays important roles in human carcinogenesis. Transcriptional levels of this gene are significantly elevated in various types of cancer including bladder and lung cancers. Immunohistochemical analysis using a number of clinical tissues confirmed significant up-regulation of WHSC1 expression in bladder and lung cancer cells at the protein level. Treatment of cancer cell lines with small interfering RNA targeting WHSC1 significantly knocked down its expression and resulted in the suppression of proliferation. Cell cycle analysis by flow cytometry indicated that knockdown of WHSC1 decreased the cell population of cancer cells at the S phase while increasing that at the G(2)/M phase. WHSC1 interacts with some proteins related to the WNT pathway including beta-catenin and transcriptionally regulates CCND1, the target gene of the beta-catenin/Tcf-4 complex, through histone H3 at lysine 36 trimethylation. This is a novel mechanism for WNT pathway dysregulation in human carcinogenesis, mediated by the epigenetic regulation of histone H3. Because expression levels of WHSC1 are significantly low in most normal tissue types, it should be feasible to develop specific and selective inhibitors targeting the enzyme as antitumor agents that have a minimal risk of adverse reaction.