Abstract
Transcription factors (TFs) engage in various cellular essential processes including differentiation, growth and migration. However, the master TF involved in distant metastasis of nasopharyngeal carcinoma (NPC) remains largely unclear. Here we show that KLF5 regulates actin remodeling to enhance NPC metastasis. We analyzed the msVIPER algorithm-generated transcriptional regulatory networks and identified KLF5 as a master TF of metastatic NPC linked to poor clinical outcomes. KLF5 regulates actin remodeling and lamellipodia formation to promote the metastasis of NPC cells in vitro and in vivo. Mechanistically, KLF5 preferentially occupies distal enhancer regions of ACTN4 to activate its transcription, whereby decoding the informative DNA sequences. ACTN4, extensively localized within actin cytoskeleton, facilitates dense and branched actin networks and lamellipodia formation at the cell leading edge, empowering cells to migrate faster. Collectively, our findings reveal that KLF5 controls robust transcription program of ACTN4 to modulate actin remodeling and augment cell motility which enhances NPC metastasis, and provide new potential biomarkers and therapeutic interventions for NPC.
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Acknowledgements
This work was supported by grants from the National Natural Science Foundation of China (92259202, 82273401, 82103579, 82102875), the Guangdong Basic and Applied Basic Research Foundation (2019A1515011863, 2019A1515012045, 2023B1515020014), the Health & Medical Collaborative Innovation Project of Guangzhou City, China (202201011261), the Special Support Program of Sun Yat-sen University Cancer Center (16zxtzlc06), the Cancer Innovative Research Program of Sun Yat-sen University Cancer Center (CIRP-SYSUCC-0010), the Young Talents Program of Sun Yat-sen University Cancer Center (YTP-SYSUCC-0069) and the Sanming Project of Medicine in Shenzhen(SZSM202211017).
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GZ and DW designed and supervised the study. GZ, DW and ZY conducted the literature search. ZY, YP, YW and PY performed the experiments. JL, ZY and XX performed the bioinformatic analysis. ZH developed the animal models. TQ, ZY, PS and YP extracted and analyzed data. GZ, ZY, DW and YS were responsible for interpreting results. ZY, YW, DW and GZ contributed to the figures and tables. ZY and DW wrote the manuscript.
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Yang, Z., Peng, Y., Wang, Y. et al. KLF5 regulates actin remodeling to enhance the metastasis of nasopharyngeal carcinoma. Oncogene (2024). https://doi.org/10.1038/s41388-024-03033-0
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DOI: https://doi.org/10.1038/s41388-024-03033-0