State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Zhongshan Hospital, Fudan University, Shanghai, 200438, China.
Department of Colorectal and Anal Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China.
Nat Commun. 2018 Oct 26;9(1):4468. doi: 10.1038/s41467-018-06812-y.
The conversion of serine and glycine that is accomplished by serine hydroxymethyltransferase 2 (SHMT2) in mitochondria is significantly upregulated in various cancers to support cancer cell proliferation. In this study, we observed that SHMT2 is acetylated at K95 in colorectal cancer (CRC) cells. SIRT3, the major deacetylase in mitochondria, is responsible for SHMT2 deacetylation. SHMT2-K95-Ac disrupts its functional tetramer structure and inhibits its enzymatic activity. SHMT2-K95-Ac also promotes its degradation via the K63-ubiquitin-lysosome pathway in a glucose-dependent manner. TRIM21 acts as an E3 ubiquitin ligase for SHMT2. SHMT2-K95-Ac decreases CRC cell proliferation and tumor growth in vivo through attenuation of serine consumption and reduction in NADPH levels. Finally, SHMT2-K95-Ac is significantly decreased in human CRC samples and is inversely associated with increased SIRT3 expression, which is correlated with poorer postoperative overall survival. Our study reveals the unknown mechanism of SHMT2 regulation by acetylation which is involved in colorectal carcinogenesis.
丝氨酸和甘氨酸的转化是由线粒体中的丝氨酸羟甲基转移酶 2（SHMT2）完成的，在各种癌症中明显上调，以支持癌细胞增殖。在这项研究中，我们观察到 SHMT2 在结直肠癌（CRC）细胞中 K95 处发生乙酰化。SIRT3 是线粒体中的主要去乙酰化酶，负责 SHMT2 的去乙酰化。SHMT2-K95-Ac 破坏其功能四聚体结构并抑制其酶活性。SHMT2-K95-Ac 还通过葡萄糖依赖性 K63-泛素-溶酶体途径促进其降解。TRIM21 作为 SHMT2 的 E3 泛素连接酶。SHMT2-K95-Ac 通过减少丝氨酸消耗和降低 NADPH 水平，在体内减弱 CRC 细胞增殖和肿瘤生长。最后，在人类 CRC 样本中，SHMT2-K95-Ac 显著降低，与 SIRT3 表达增加呈负相关，这与术后总生存期较差相关。我们的研究揭示了 SHMT2 乙酰化调节的未知机制，该机制参与了结直肠癌的发生。
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