WHSC1 Promotes Oncogenesis through Regulation of NIMA-Related Kinase-7 in Squamous Cell Carcinoma of the Head and Neck
WHSC1 Promotes Oncogenesis through Regulation of NIMA-Related Kinase-7 in Squamous Cell Carcinoma of the Head and Neck
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DOI：
10.1158/1541-7786.mcr-14-0292-t
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发表时间：
2015-02-01
影响因子：
5.2
通讯作者：
Hamamoto, Ryuji
中科院分区：
文献类型：
--
作者：
Saloura, Vassiliki;Cho, Hyun-Soo;Hamamoto, Ryuji
头颈部鳞状细胞癌（SCCHN）是一种相对常见的恶性肿瘤，长期预后不佳，因此迫切需要新的治疗策略。在过去的十年中，组蛋白甲基转移酶（HMT）已被公认为癌症治疗的有前途的目标，但其在大多数实体瘤，包括SCCHN中的作用机制仍有待阐明。本研究探讨了Wolf-Hirschhorn综合征候选者1（WHSC 1），一个NSD家族HMT，在SCCHN中的作用。局部晚期SCCHN、异型增生和正常上皮组织标本的免疫组化分析显示，WHSC 1表达和组蛋白H3赖氨酸36（H3 K36 me 2）的二甲基化在SCCHN组织中显著高于正常上皮。WHSC 1表达和H3 K36 me 2表达水平与组织学分级显著相关。多个SCCHN细胞系中的WHSC 1敲除导致显着的生长抑制、诱导细胞凋亡和细胞周期进程延迟。免疫印迹和免疫细胞化学分析表明，WHSC 1诱导H3 K36 me 2和H3 K36 me 3。基因芯片表达谱分析表明，NIMA相关激酶7（NEK 7）是WHSC 1的下游靶基因，染色质免疫沉淀（ChIP）分析表明，NEK 7通过H3 K36 me 2直接受WHSC 1调控。此外，与WHSC 1类似，NEK 7敲低显著降低了细胞周期进程，表明NEK 7是WHSC 1调控的分子途径中的关键参与者。(C)2014年AACR。
Squamous cell carcinoma of the head and neck (SCCHN) is a relatively common malignancy with suboptimal long-term prognosis, thus new treatment strategies are urgently needed. Over the last decade, histone methyltransferases (HMT) have been recognized as promising targets for cancer therapy, but their mechanism of action in most solid tumors, including SCCHN, remains to be elucidated. This study investigated the role of Wolf-Hirschhorn syndrome candidate 1 (WHSC1), an NSD family HMT, in SCCHN. Immunohistochemical analysis of locoregionally advanced SCCHN, dysplastic, and normal epithelial tissue specimens revealed that WHSC1 expression and dimethylation of histone H3 lysine 36 (H3K36me2) were significantly higher in SCCHN tissues than in normal epithelium. Both WHSC1 expression and H3K36me2 levels were significantly correlated with histologic grade. WHSC1 knockdown in multiple SCCHN cell lines resulted in significant growth suppression, induction of apoptosis, and delay of the cell-cycle progression. Immunoblot and immunocytochemical analyses in SCCHN cells demonstrated that WHSC1 induced H3K36me2 and H3K36me3. Microarray expression profile analysis revealed NIMA-related kinase-7 (NEK7) to be a downstream target gene of WHSC1, and chromatin immunoprecipitation (ChIP) assays showed that NEK7 was directly regulated by WHSC1 through H3K36me2. Furthermore, similar to WHSC1, NEK7 knockdown significantly reduced cell-cycle progression, indicating that NEK7 is a key player in the molecular pathway regulated by WHSC1. (C) 2014 AACR.