P53 Promotes Peroxisome Fatty Acid β Oxidation And Inhibits Colorectal Cancer Via VDR

Colorectal cancer((Colorectal Cancer,CRC))is a malignant digestive tract tumor with high morbidity and mortality in all kinds of cancers in the world,which seriously threatens human life and health and affects the quality of life of patients.At present,however,there is no completely effective treatment that can completely cure colorectal cancer.Therefore,it is an important task and an urgent problem to study thoroughly the pathogenesis of colorectal cancer and develop effective treatment according to its mechanism.P53 tumor suppressor is not only an important transcriptional factor in cells,but also an important intracellular stress receptor,which can regulate a variety of cell life activities such as cell cycle,apoptosis,metabolism and immune response,and it is prone to mutation in tumor tissue.Because of the importance of p53 and its mutational nature,P53 has become the focus of research.Fatty acid β oxidation is an important process of intracellular fatty acid metabolism,which is an essential lipid substance for cells.At the same time,it can also produce a large amount of ATP for cell life activities.In this study,the case data of colorectal cancer in TCGA database were divided into p53 wild type group and p53 mutant group.114 metabolic rate-limiting enzymes in cell metabolism were enriched in the two groups,and the differential expression multiple and P value of these rate-limiting enzymes in colorectal cancer were analyzed.There are5 genes with significant differences in expression between p53 wild type group and p53 mutant group were found.Through pan-cancer analysis,we found that peroxisome fatty acid β oxidation pathway rate-limiting enzyme ACOX1 was significantly low expressed in many kinds of cancers and affected the survival risk of cancer patients.In addition,the expression level and protein content of ACOX1 in colorectal cancer tissues were analyzed in GEO database,HPA and CTPAC protein database.At the same time,the survival rate of colorectal cancer patients in TCGA database was analyzed.The results showed that the expression and protein level of ACOX1 in tumor tissues decreased significantly.Our study also found that in addition to ACOX1,the expression of ABCD3,ABCD4 and EHHADH related to peroxisome fatty acid β oxidation pathway was also regulated by p53.Through correlation analysis,it was found that there was no significant correlation between p53 and these four genes.Therefore,we analyzed the correlation between the known transcription factors and ACOX1,ABCD3,ABCD4 and EHHADH,and found the transcription factor VDR which can bind to the promoter regions of these four genes through overlap and comparison.Through Co-IP experiment,the results showed that VDR recruited p53 through the CTD domain of p53 to regulate the expression of enzymes related to peroxisome fatty acid β oxidative metabolism pathway.In addition,MTT assay showed that overexpression of peroxisome fatty acid βoxidation genes(ACOX1,ABCD3,ABCD4,EHHADH)significantly inhibits tumor growth in colorectal cancer cell lines(HCT116 and RKO).In short,our research shows that VDR can recruit p53 to promote the expression of peroxisome fatty acid β oxidation genes(ACOX1,ABCD3,ABCD4,EHHADH),promote fatty acid β oxidation,and inhibit the occurrence of colorectal cancer.Bioinformatics analysis also found that the expression of these genes was significantly low during colorectal carcinogenesis,suggesting the inhibitory effect of peroxisome fatty acid β oxidation on colorectal carcinogenesis.These studies may provide potential therapeutic targets for colorectal cancer.