The Expression Of SIRT4 In Gastrointestinal Carcinoma And Its Effect On Human Colorectal Cancer Cell Strains’ Biological Behavior Study

Background: The SIRT family(SIRT1-7) is an NAD+- dependent deacetylase, histone acetylation enzyme and ADP- ribosyltransferase family. Almost all of the members of SIRT family are thought to play an important role in tumor formation. Recent studies show that SIRT4 can regulate the glutamine metabolism thus acts as a tumor suppressor in human cancer. But there is no study reveal the relationship between SIRT4 and human cancer based on cancer tissues expecially at the protein level.Methods: We analyzed the mRNA expression levels of SIRT4 in 16 paired colorectal cancer and adjacent normal colon tissue specimens by RT-PCR and TCGA database which contains 223 cases of human colon cancer samples. We then performed immunohistochemistry experiment on tissue chips which include 89 cases of colon cancer tissues and 75 cases of gastric cancer, respectively. And then, weanalyzed the relationship between the expression of SIRT4 with the clinical pathological parameters of colorectal cancer and gastric cancer patients. We constructed the stable strains of human colon cancer cells RKO and HT29 which overexpressed SIRT4. We studied the influence of SIRT4 overexpression on the proliferation and clone formation of RKO and HT29 cell, and we further analyzed the impact of SIRT4 overexpression on the sensitivity of these cells to glucose metabolic inhibitors and 5-FU. We also analyzed the survival rate of of RKO and HT29 cells with SIRT4 overexpression in glutamine depletion medium.Results: The expression of SIRT4 in colorectal cancer and gastric cancer tissues was significantly lower than that in adjacent normal tissues, the decreased expression of SIRT4 is strongly correlated with the worse degree of pathological differentiation of colorectal cancer and gastric cancer(p=0.01, p=0.002, respectively), and the decreased expression of SIRT4 in patients with colorectal cancer appear decreased 5 years survival rate. Overexpression of SIRT4 inhibited the proliferation of RKO and HT29 cells, increased their sensitivity to the glucose metabolic inhibitors(2-DG) as well as 5-FU, and reduced the survival rate of RKO and HT29 cells in glutamine deprivation culture medium.Conclusion: SIRT4 act as a tumor suppressor in human colorectal cancer and gastric cancer. SIRT4 is a promising diagnosis marker for human colorectal cancer and gastric cancer, and is a good therapeutic target for colorectal cancer.