Polo-Like Kinase 1 phosphorylates and stabilizes KLF4 to promote tumorigenesis in nasopharyngeal carcinoma
Polo-Like Kinase 1 phosphorylates and stabilizes KLF4 to promote tumorigenesis in nasopharyngeal carcinoma
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Polo 样激酶 1 磷酸化并稳定 KLF4 促进鼻咽癌肿瘤发生
DOI：
10.7150/thno.32908
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发表时间：
2019-01-01
期刊：
影响因子：
12.4
通讯作者：
Zhu, Xiao-Feng
中科院分区：
文献类型：
--
作者：
Mai, Jia;Zhong, Zhuo-Yan;Zhu, Xiao-Feng
理由：晚期鼻咽癌（NPC）是一种侵袭性疾病，没有靶向治疗且预后不佳。迫切需要新的创新目标。 KLF4 已在肿瘤背景下进行了广泛研究，目前的数据表明它可以充当组织特异性肿瘤抑制基因或肿瘤促进基因。在这里，我们发现KLF4在鼻咽癌中发挥促癌基因的作用，并且可以由PLK1介导。方法：采用组织免疫组织化学 (IHC) 检测来鉴定 KLF4 在 NPC 中的作用。进行全局基因表达实验以探索 KLF4 依赖性肿瘤发生的分子机制。进行小分子激酶抑制剂筛选以确定 KLF4 的潜在上游激酶。测定了 Polo 样激酶抑制剂 volasertib (BI6727) 的体外和体内药理活性。结果：我们的研究表明，KLF4 的高表达与鼻咽癌的不良预后相关。此外，全基因组分析显示，KLF4 直接激活致癌程序，包括与 KRAS、VEGF 和 MYC 信号传导相关的基因集。我们进一步发现抑制polo样激酶1可以下调KLF4的表达，并且PLK1直接磷酸化KLF4的Ser234位点。值得注意的是，PLK1 对 KLF4 的磷酸化导致 E3 连接酶 TRAF6 的招募和结合，从而导致 KLF4 K32 K63 连接的泛素化和稳定化。此外，KLF4可以在转录水平增强TRAF6表达，从而启动KLF4-TRAF6前馈循环。用 PLK1 抑制剂 volasertib (BI6727) 治疗可显着抑制裸鼠的肿瘤生长。结论：我们的研究揭示了一种新的 PLK1-TRAF6-KLF4 前馈环路。由此产生的 KLF4 泛素化增加导致 KLF4 稳定和上调，从而导致 NPC 肿瘤发生。这些结果扩展了我们对 KLF4 在 NPC 中作用的理解，并验证 PLK1 抑制剂作为 NPC，特别是 KLF4 过表达的癌症患者的潜在治疗药物。
Rationale: Advanced nasopharyngeal carcinoma (NPC) is an aggressive disease with no targeted therapies and poor outcomes. New innovative targets are urgently needed. KLF4 has been extensively studied in the context of tumors, and current data suggest that it can act as either a tissue-specific tumor-inhibiting or a tumor-promoting gene. Here, we found that KLF4 played as a tumor-promoting gene in NPC, and could be mediated by PLK1. Methods: Tissue immunohistochemistry (IHC) assay was performed to identify the role of KLF4 in NPC. Global gene expression experiments were performed to explore the molecular mechanisms underlying KLF4-dependent tumorigenesis. Small-molecule kinase inhibitor screening was performed to identify potential upstream kinases of KLF4. The pharmacologic activity of polo-like kinase inhibitor volasertib (BI6727) in vitro and in vivo was determined. Result: Our investigation showed that high expression of KLF4 was correlated with poor prognosis in NPC. Moreover, genome-wide profiling revealed that KLF4 directly activated oncogenic programmes, including gene sets associated with KRAS, VEGF, and MYC signalling. We further found that inhibition of polo-like kinase 1 could downregulate the expression of KLF4 and that PLK1 directly phosphorylated KLF4 at Ser234. Notably, phosphorylation of KLF4 by PLK1 caused the recruitment and binding of the E3 ligase TRAF6, which resulted in KLF4 K32 K63-linked ubiquitination and stabilization. Moreover, KLF4 could enhance TRAF6 expression at the transcriptional level, thus initiating a KLF4-TRAF6 feed-forward loop. Treatment with the PLK1 inhibitor volasertib (BI6727) significantly inhibited tumor growth in nude mice. Conclusion: Our study unveiled a new PLK1-TRAF6-KLF4 feed-forward loop. The resulting increase in KLF4 ubiquitination leads to stabilization and upregulation of KLF4, which leads to tumorigenesis in NPC. These results expand our understanding of the role of KLF4 in NPC and validate PLK1 inhibitors as potential therapeutic agents for NPC, especially cancer patients with KLF4 overexpression.