Scientists have revealed that the longevity gene SIRT3 regulates the mechanisms of colorectal cancer

In collaboration with Professor Cui Long of Xinhua Hospital, affiliated with Shanghai Jiaoda University School of Medicine, Yu Yu, researchers at Fudan University's School of Life Sciences found that the longevity gene SIRT3 regulates the participation of a carbon unit metabolic enzyme in the new molecular mechanism of colorectal cancer, providing a solid theoretical basis for the development of targeted drugs for the treatment of colorectal cancer. The results of the study were published online in Nature Communications.
colorectal cancer is one of the most common types of gastrointestinal malignancies in the world. With the improvement of national living standards and lifestyle changes, the incidence and mortality rate of colorectal cancer is increasing year by year, and China has become the country with the largest number of new cases of colorectal cancer in the world every year. At present, the treatment of colorectal cancer mainly depends on surgical removal of tumor combination, chemotherapy and other means. It is necessary to seek new diagnostic methods, drug targets and prognostic interventions, starting from the pathogenic mechanism of colorectal cancer and the factors of genetic, oscic genetic and metabolic factors that affect the progression of the disease.
researchers found that mitochondrial primary deacetylase SIRT3, in the case of glucose hunger, can directly bind to a key metabolic enzyme in a carbon unit metabolic pathline - syrine hydroxymethyl transferase 2 (SHMT2), and can remove SHMT2 K95 acetylation modification, stabilize the intracellular expression of SHMT2 and maintain the high activity of SHMT2. SHMT2 is mainly responsible for the conversion of intracellular serine and glycine, highly active SHMT2 can help cells resist the reactive oxygen pressure of mitochondrials, and ensure the supply of biological molecules in cells to meet the needs of rapid proliferation of cancer cells.
researchers found in samples of colorectal cancer patients that SIRT3 and SHMT2 were co-expressed highly, with correspondingly low acetylation of SHMT2 K95. Colorectal cancer patients with high expression sirT3 or SHMT2 had low overall postoperative survival and poor prognostication. Acetylation modification of SHMT2 K95 promotes the binding of E3 connective enzyme TRIM21 and causes Acetylized SHMT2 to degrade through the macro-autophagy pathway of K63 polysactin dependence. This modification also impairs the rate of proliferation and tumorization of colorectal cancer cells. In the induced mouse enteritis model, the absence of the Sirt3 gene significantly reduced the size and number of tumors in the mouse's small intestine. Immunogroup staining showed a significant reduction in the expression of SHMT2 in the tumor cells of Sirt3 knock-out mice. In this study, the structure analysis of SHMT2 mutants was carried out, and it was found that SHMT2 K95 mutated into R/Q, which destroyed the complete functional tymer structure of SHMT2, thus reducing its affinity for substrate serine and reducing the activity of enzymes. This study reveals the role of sirT3-SHMT2 regulatory axis in the development of colorectal cancer, and provides a solid theoretical basis for the development of targeted drugs targeting SIRT3-SHMT2 regulatory axis for the treatment of colorectal cancer.
it is understood that Fudan University is the first completion unit for the work. Yu Wei Group Ph.D. student Wei Zhen and Cui Long Group Ph.D. student Song Jing slightly as the co-first author of this article. Yu Wei of Fudan University and Cui Long and Liu Chenying, associate researchers of Xinhua Hospital affiliated with Shanghai Jiaozhou University School of Medicine, are co-authors of the newsletter. Professor Li Jixi of Fudan University's School of Life Sciences is the co-author of the study, which provides analysis of the crystal structure of SHMT2 mutants. (Source: Science Network Huang Xin)