一碳单位代谢通路的许多代谢酶与肿瘤的发生、发展都有着密切关系。前期研究中发现，一碳单位通路中包括丝氨酸羟甲基转移酶2（SHMT2）在内的数个关键代谢酶，在结直肠癌中表达量都有显著的提高，且高表达SHMT2的结直肠癌患者的术后总体生存率显著下降。这些都提示SHMT2在结直肠癌的发生发展中起到很重要的作用，但具体的机制并不清楚。我们的初步数据表明在去乙酰化酶抑制剂处理下SHMT2高度乙酰化修饰，且SIRT3是其去乙酰化酶。SHMT2的乙酰化修饰既抑制酶活性，又促进蛋白的降解，并与结直肠癌细胞的增殖有紧密联系。本项目探索一碳单位通路代谢酶SHMT2的乙酰化修饰机制，采用细胞生物学、生物化学手段结合临床患者数据，揭示SHMT2的乙酰化修饰对其酶活、稳定性以及一碳单位下游代谢产物水平的影响，阐明SHMT2参与结直肠癌的分子机理和生物效应。本课题有望为结直肠癌的治疗和临床诊断提供潜在的药物靶点。

An amount of enzymes in one carbon metabolism pathway are deeply involved in tumorigenesis. Notably three enzymes, including serine hydroxymethyltransferase 2 (SHMT2), are significantly upregulated in colorectal cancer comparing with normal tissues. Moreover, high expression of SHMT2 is correlated with poor postoperative survival of patients. These data indicate SHMT2 plays a significant role in colorectal cancer carcinogenesis. However, the regulation mechanism of SHMT2 in colorectal cancer carcinogenesis remains unknown. Our preliminary data suggested that SHMT2 was highly acetylated in vivo under deacetylase inhibitors and SIRT3, a NAD+-dependent deacetylase, was the major deacetylase for SHMT2. Strikingly, acetylation inhibits the enzymatic activity of SHMT2 and promotes its protein degradation, which is significantly linked with the proliferation of colorectal cancer cells. In this study, we will illuminate the mechanism of acetylation regulation SHMT2 in colorectal cancer carcinogenesis. The biological function of SHMT2 enzymatic activity and its protein stability will be determined. Moreover, the metabolomics of one carbon metabolism pathway will be explored. We will combine the molecular mechanism with clinical data to elucidate the progression of SHMT2 in colorectal cancer carcinogenesis. Our study will reveal the acetylation regulation mechanism of SHMT2 in tumorigenesis, providing the potential drug targets for the diagnosis and treatment of colorectal cancer.