PHF5A regulates the expression of the DOCK5 variant to promote HNSCC progression through p38 MAPK activation

Abstract

BackgroundPreviously, we identified an oncogenic splicing variant of DOCK5 in head and neck squamous cell carcinoma (HNSCC); however, the mechanism for the generation of this specific DOCK5 variant remains unknown. This study aims to explore the potential spliceosome genes involved in the production of the DOCK5 variant and validate its role in regulating the progression of HNSCC.MethodsThe differentially expressed spliceosome genes involved in the DOCK5 variant were analysed in The Cancer Genome Atlas (TCGA), and the correlation between the DOCK5 variant and the potential spliceosome gene PHF5A was verified by qRT-PCR. The expression of PHF5A was detected in HNSCC cells, TCGA data and a separate primary tumour cohort. The functional role of PHF5A was examined using CCK-8, colony formation, cell scratch and Transwell invasion assays in vitro and validated in vivo in xenograft models of HNSCC. Western blot analysis was used to explore the potential mechanism of PHF5A in HNSCC.ResultsPHF5A was one of the top upregulated spliceosome genes in TCGA HNSCC samples with highly expressed DOCK5 variants. Knockdown or overexpression of PHF5A in HNSCC cells correspondingly altered the level of the DOCK5 variant. PHF5A was highly expressed in tumour cells and tissues and correlated with a worse prognosis of HNSCC. Loss- and gain-of-function experiments demonstrated that PHF5A could promote the proliferation, migration and invasion of HNSCC cells in vitro and in vivo. Moreover, PHF5A inhibition reversed the oncogenic effect of the DOCK5 variant in HNSCC. Western blot analysis showed that PHF5A activated the p38 MAPK pathway, and inhibition of p38 MAPK further reversed the effect of PHF5A on the proliferation, migration and invasion of HNSCC cells.ConclusionPHF5A regulates the alternative splicing of DOCK5 to promote HNSCC progression through p38 MAPK activation, which provides potential therapeutic implications for HNSCC patients.