The Function Of PAK6 And Its Mechanism Of Dysregulation In Colorectal Cancer

PAK6 is a member of the p21-activated kinase family,which is a class of serine / threonine protein kinase.Since PAK6 was discovered,more and more research has focused on PAK6 biological function and mechanism.Recent studies revealed that PAK6 was highly expressed in the testis,liver and prostate tissue.PAK6 could decrease chemotherapy sensitivity of docetaxel and sensitivity to radiation in prostate cancer.However,the expression of PAK6 and its clinical significance in colorectal cancer is still lack of relevant research,especially for PAK6’s mechanism and transcriptional regulation in the development and treatment of the CRC.In the present study,we found that PAK6 was highly expressed in CRC.The expression of PAK6 is correlated with differentiation and CRC recurrence after postoperative chemotherapy.Patients with high expression of PAK6 showed poor prognosis.In vivo experiments,we demonstrated that overexpression of PAK6 can promote cell proliferation and invasion,While knocking down PAK6 weakened proliferation and invasion.Subsequently,through Microarray expression profiling,we found that a number of PAK6 regulatated genes was involved in the MAPK/ERK signaling pathway.Subsequent experiments confirmed that knocking down PAK6 would reduce phosphorylation of ERK and decrease the expression of its downstream target c-Myc and MMP9.We speculated PAK6 may promotes proliferation and invasion of CRC by activating the MAPK / ERK pathway.In addition,we found that PAK6 was increased in 5-FU treated CRC cells.Overexpression of PAK6 reduce 5-FU-induced apoptosis.While knocking down PAK6 increased 5-FU-induced apoptosis.Further studies showed that PAK6 increase phosphorylation of BAD,an apoptosis-related protein,thus promoted CRC cells against apoptosis induced by 5-FU,resulting in resistance to chemotherapy of CRC.Finally,we found that there are three binding sites for transcription factor OCT1 in PAK6 promoter.We found that OCT1 was highly expressed in CRC,and can significantly promote tumor proliferation.By designing OCT1 overexpression plasmid and PAK6 promoter reporter plasmid,we examined the promoter activity of PAK6,which showed that OCT1 can significantly enhance transcriptional activity PAK6.Therefore,we believe that PAK6 could be regulated by OCT1 in translational level.