CDK1 Interacts with Sox2 and Promotes Tumor Initiation in Human Melanoma.
CDK1 Interacts with Sox2 and Promotes Tumor Initiation in Human Melanoma.
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DOI：
10.1158/0008-5472.can-18-0330
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发表时间：
2018-12-01
期刊：
影响因子：
11.2
通讯作者：
Fujita M
中科院分区：
文献类型：
--
作者：
Ravindran Menon D;Luo Y;Arcaroli JJ;Liu S;KrishnanKutty LN;Osborne DG;Li Y;Samson JM;Bagby S;Tan AC;Robinson WA;Messersmith WA;Fujita M
癌症由具有不同肿瘤启动能力的异质亚群组成，但与增强肿瘤启动能力相关的关键干细胞基因及其调节机制仍然难以捉摸。在这里，我们分析了来自黑色素瘤、结肠癌和胰腺癌组织的患者来源的异种移植物，并鉴定了 MHC I-hi 细胞中肿瘤起始细胞的富集，其中细胞周期的主要调节因子 CDK1 上调。黑色素瘤细胞中 CDK1 的过表达（而非其激酶死亡变体）增加了其球状体形成能力、致瘤潜力和肿瘤启动能力；用药物抑制 CDK1 会降低这些特征，这是 CDK1 在调节细胞周期中的作用无法解释的。蛋白质组学分析揭示了 CDK1 和多能干细胞转录因子 Sox2 之间的相互作用。 CDK1 的阻断或敲低会导致 Sox2 的磷酸化、核定位和转录活性降低。 CDK1 过表达细胞中 Sox2 的敲除显着降低了 CDK1 驱动的肿瘤启动能力。此外，CDK1-hi 肿瘤细胞的 GSEA 分析发现了所有三种癌症类型中常见的通路特征，包括 E2F、G2M、MYC 和精子发生，证实了 CDK1-hi 肿瘤细胞的干细胞样性质。这些发现揭示了 CDK1 在调节黑色素瘤肿瘤启动能力中先前未被认识的作用，并提出了一种通过中断 CDK1 功能及其蛋白质-蛋白质相互作用来治疗癌症的新策略。
Cancers are comprised of heterogeneous subpopulations with various tumor-initiating capacities, yet key stem cell genes associated with enhanced tumor initiating capacities and their regulatory mechanisms remain elusive. Here we analyzed patient-derived xenografts from melanoma, colon, and pancreatic cancer tissues and identified enrichment of tumor-initiating cells in MHC class I-hi cells, where CDK1, a master regulator of the cell cycle, was upregulated. Overexpression of CDK1, but not its kinase-dead variant, in melanoma cells increased their spheroid forming ability, tumorigenic potential, and tumor-initiating capacity; inhibition of CDK1 with pharmacological agents reduced these characteristics, which was unexplained by the role of CDK1 in regulating the cell cycle. Proteomic analysis revealed an interaction between CDK1 and the pluripotent stem cell transcription factor Sox2. Blockade or knockdown of CDK1 resulted in reduced phosphorylation, nuclear localization, and transcriptional activity of Sox2. Knockout of Sox2 in CDK1-overexpressing cells reduced CDK1-driven tumor-initiating capacity substantially. Furthermore, GSEA analysis of CDK1-hi tumor cells identified a pathway signature common in all three cancer types, including E2F, G2M, MYC, and spermatogenesis, confirming a stem-like nature of CDK1-hi tumor cells. These findings reveal a previously unrecognized role for CDK1 in regulating tumor-initiating capacity in melanoma and suggest a novel treatment strategy in cancer via interruption of CDK1 function and its protein-protein interactions.