SHMT2琥珀酰化抗结直肠癌的机制研究及药物筛选

Tumor cells often promote rapid proliferation through modulating their metabolic processes such as the serine catabolism. Accumulating evidence indicates that mitochondrial serine hydroxymethyltransferase (SHMT2), which catalyzes the rate-limiting step in serine catabolism, plays a key role in cancer cell growth. We have found that SIRT5 can interact and desuccinylate SHMT2 and upregulate its enzymatic activity. Cells with hypersuccinylated SHMT2 induce serine accumulation, increased ROS levels, and reduced proliferation rates of colorectal cancer cells. Based on above results, we will further study: 1, Investigate the downstream pathways which affected by hypersuccinylated SHMT2 induced slower cell proliferation; 2, Identify the competitive inhibitors which specifically bind to succinylation sites of SHMT2; 3, Identify and confirm the targeted therapy drugs for colorectal cancer based on SHMT2 K280 succinylation site. Our study will provide a new insight for colorectal cancer targeted therapy and develop a potential new drug for the treatment of colorectal cancer.

丝氨酸代谢作为一种重要的代谢通路是恶性肿瘤为适应其快速生长所必需的。探究丝氨酸分解代谢的限速酶SHMT2的琥珀酰化修饰在调控肿瘤细胞代谢重编程中的具体机制目前已经引起广泛的关注。本课题组最新发现SIRT5能够与SHMT2结合并对其进行去琥珀酰化修饰从而上调SHMT2的酶活性，SHMT2高琥珀酰化能导致丝氨酸的积累，氧化的不稳定性以及结直肠癌细胞增殖能力的减弱。我们将在以上的实验基础上进行更深入的研究：1.探究高琥珀酰化SHMT2造成的细胞增殖减慢的下游通路；2.寻找能够在SHMT2 琥珀酰化位点上与PLP竞争性结合的特异性抑制剂；3.寻找及验证基于SHMT2 K280位点可行的抑制结直肠癌发生的药物。本课题将通过研究SHMT2琥珀酰化修饰导致的代谢重编程的机制，为结直肠癌的靶向性治疗提供理论基础和初步探索。

丝氨酸代谢作为一种重要的代谢通路是恶性肿瘤为适应其快速生长所必需的。探究丝氨酸分解代谢的限速酶SHMT2的琥珀酰化修饰在调控肿瘤细胞代谢重编程中的具体机制目前已经引起广泛的关注。本课题组最新发现SIRT5能够与SHMT2结合并对其进行去琥珀酰化修饰从而上调SHMT2的酶活性，SHMT2高琥珀酰化能导致丝氨酸的积累，氧化的不稳定性以及结直肠癌细胞增殖能力的减弱。我们在以上的实验基础上进行更深入的研究：1.探究了高琥珀酰化SHMT2造成的细胞增殖减慢的下游通路；2.对SHMT2 琥珀酰化造成的一碳循环变化导致S-Adenosyl methionine (SAM)量的变化从而影响细胞染色质整体甲基化水平进行了研究。本课题通过研究SHMT2琥珀酰化修饰导致的代谢重编程的机制，为结直肠癌的靶向性治疗提供了理论基础。