Abstract:
Oral squamous cell carcinoma (OSCC) accounts for 90% of all malignancies in the oral cavity and is associated with poor prognosis and survival, especially in individuals with recurrent or metastatic cancer. Thus, it is imperative that potential new druggable targets are studied to allow for the development of more effective treatment. To this end, p21-activated kinase 4 (PAK4) is of interest as its overexpression has been associated to poor prognosis in a subset of OSCC patients. However, while functional studies on PAK4 have been carried out in ovarian, pancreatic, breast, and glioma cell line models, the mechanisms underlying PAK4 activity in OSCC have yet to be delineated.
This study has shown that depletion of PAK4 by RNAi-mediated silencing conferred reduced cell motility, and survival in OSCC cell lines. It is also demonstrated that global proteomic and phosphoproteomic profiling of RNAi-mediated PAK4 depletion results in significant perturbations to mRNA splicing factors (SRSF2, SRSF5, SRSF6), proteasome activator subunits (PSME1-4), and 97 phosphoproteins, including the dephosphorylation of proteins involved in MAPK signalling (e.g. SHC1, PEA15, MAPK6), Ras signalling (e.g. NF1, ETS1, RASAL2), and epithelial-mesenchymal transition (ETS1 and VIME) as novel targets of PAK4. Indeed, knockdown of PAK4 perturbs splicing activity in PAK4-depleted OSCC cells, resulting in aberrant intron retention. Medium and low PAK4 expression, too, affects spliceosome activities of a handful of oncogenic genes in primary tumours (SpliceSeq). In conclusion, the results suggest that PAK4 influences mRNA splicing and the proteasome pathway; and since these relationships have yet to be demonstrated, these findings warrant further studies in unravelling the roles of PAK4.
