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.