Deacetylation of serine hydroxymethyl-transferase 2 by SIRT3 promotes colorectal carcinogenesis.
Deacetylation of serine hydroxymethyl-transferase 2 by SIRT3 promotes colorectal carcinogenesis.
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SIRT3 对丝氨酸羟甲基转移酶 2 的去乙酰化可促进结直肠癌的发生。
DOI：
10.1038/s41467-018-06812-y
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发表时间：
2018-10-26
影响因子：
16.6
通讯作者：
Yu W
中科院分区：
文献类型：
--
作者：
Wei Z;Song J;Wang G;Cui X;Zheng J;Tang Y;Chen X;Li J;Cui L;Liu CY;Yu W
丝氨酸和甘氨酸的转换是由线粒体中的丝氨酸羟甲基转移酶2(SHMT2)完成的，在各种癌症中显著上调，以支持癌细胞的增殖。在这项研究中，我们观察到SHMT2在结直肠癌(CRC)细胞中在K95处被乙酰化。SIRT3是线粒体中主要的脱乙酰酶，负责SHMT2的脱乙酰基作用。SHMT2-K95-Ac破坏其功能四聚体结构，抑制其酶活性。SHMT2-K95-Ac还通过K63-泛素-溶酶体途径以葡萄糖依赖的方式促进其降解。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水平来减少体内CRC细胞的增殖和肿瘤生长。最后，SHMT2-K95-Ac在人类结直肠癌样本中显著降低，并与SIRT3表达增加呈负相关，这与较差的术后总存活率相关。我们的研究揭示了乙酰化调控SHMT2的未知机制，该机制参与了结直肠癌的发生。丝氨酸羟甲基转移酶2(SHMT2)在线粒体中将丝氨酸转化为甘氨酸，在多种癌症中表达上调。在这里，作者表明，赖氨酸-95(K95)残基的乙酰化在结直肠癌中负向调节SHMT2的表达和活性，并被SIRT3去乙酰化。
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. Serine hydroxymethyltransferase 2 (SHMT2) converts serine to glycine in mitochondria and is upregulated in a variety of cancers. Here the authors show that acetylation of the lysine-95 (K95) residue negatively regulates SHMT2 expression and activity and is deacetylated by SIRT3 in colorectal cancer.
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影响因子：
16
作者：
Elia AE;Boardman AP;Wang DC;Huttlin EL;Everley RA;Dephoure N;Zhou C;Koren I;Gygi SP;Elledge SJ
通讯作者：
Elledge SJ
SIRT3 线粒体脱乙酰酶在细胞生理学、癌症和神经退行性疾病中的功能。
影响因子：
7.8
作者：
Ansari A;Rahman MS;Saha SK;Saikot FK;Deep A;Kim KH
通讯作者：
Kim KH
影响因子：
16
作者：
Avalos, JL;Bever, KM;Wolberger, C
通讯作者：
Wolberger, C
DOI：
10.1073/pnas.1706617114
发表时间：
2017-10-24
影响因子：
11.1
作者：
Ducker, Gregory S.;Ghergurovich, Jonathan M.;Rabinowitz, Joshua D.
通讯作者：
Rabinowitz, Joshua D.
影响因子：
64.5
作者：
Inuzuka H;Gao D;Finley LW;Yang W;Wan L;Fukushima H;Chin YR;Zhai B;Shaik S;Lau AW;Wang Z;Gygi SP;Nakayama K;Teruya-Feldstein J;Toker A;Haigis MC;Pandolfi PP;Wei W
通讯作者：
Wei W