SIRT1 Suppresses Colorectal Cancer Metastasis By Transcriptional Repression Of MiR-15b-5p

Colorectal cancer(CRC)is the third most commonly diagnosed malignancy and the fourth leading cause of cancer death in the world.There were significant regional differences in the incidence of the disease,the high incidence area is mainly concentrated in North America and other developed countries.With the development of the economy and the change of people’s lifestyle,diet and habits,the incidence of colorectal cancer showed an increasing trend in the world.The etiology and mechanisms of colorectal cancer is connected with environmental,genetics,chronic inflammation and other adverse factors.Although significant achievements have been made in the prevention and treatment,approximately 20% of all CRC patients are diagnosed with primary metastatic disease.So far,the diagnosis for recurrent and metastasis of CRC is still a major difficulty,and it is needed to identify new biomarkers in CRC in order to better treatment for CRC patients.Silent mating type information regulation 2 homolog-1(SIRT1)is a NAD + dependent class III deacetylase which can deacetylate both histone and non-histone proteins.SIRT1 also has an impact on senescence,differentiation and oxidative stress.In addition,SIRT1 is considered as an essential role in tumorigenesis.Recent studies demonstrate that SIRT1 is overexpressed in some cancers,however,the function of SIRT1 in tumor initiation and progression is still controversial.SIRT1 might act as a tumor promoter by inhibiting tumor suppressor genes such as p53,but SIRT1 might also act as a tumor suppressor by repressing several oncogenes or cancer-related proteins.Here we report that SIRT1 suppressed CRC metastasis in vitro and in vivo as a negative regulator for mi R-15b-5p transcription.Mechanistically,SIRT1 impaired regulatory effects of activator protein(AP-1)on mi R-15b-5p trans-activation through deacetylation of AP-1.Importantly,acyl-Co A oxidase 1(ACOX1),a key enzyme of the fatty acid oxidation(FAO)pathway,was found as a direct target for mi R-15b-5p.SIRT1 expression was positively correlated with ACOX1 expression in CRC cells and in xenografts.Moreover,ACOX1 overexpression attenuated the augmentation of migration and invasion of CRC cells by SIRT1 overexpression.In conclusion,our study demonstrated a functional role of the SIRT1/mi R-15b-5p/ACOX1 axis in CRC metastasis and suggested a potential target for metastatic CRC therapy.