Glucose-sensitive acetylation of Seryl tRNA synthetase regulates lipid synthesis in breast cancer.
Glucose-sensitive acetylation of Seryl tRNA synthetase regulates lipid synthesis in breast cancer.
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Seryl tRNA 合成酶的葡萄糖敏感性乙酰化调节乳腺癌中的脂质合成
DOI：
10.1038/s41392-021-00714-0
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发表时间：
2021-08-16
影响因子：
39.3
通讯作者：
Shi Y
中科院分区：
文献类型：
--
作者：
Zhao J;Bai H;Li X;Yan J;Zou G;Wang L;Li X;Liu Z;Xiang R;Yang XL;Shi Y
脂质从头合成的异常增强在包括乳腺癌在内的多种癌症的发生和发展中起着至关重要的作用。然而，乳腺癌中脂质生物合成失调的潜在机制在很大程度上仍然未知。本文报道了蛋白质生物合成的关键酶丝氨酰tRNA合成酶（SerRS）能够以葡萄糖依赖的方式进入细胞核，抑制脂质从头合成的关键基因。在正常乳腺上皮细胞中，葡萄糖可通过增加SerRS在赖氨酸323处的乙酰化来促进SerRS的核转位。在SerRS基因敲入小鼠的乙酰化缺陷赖氨酸精氨酸突变，我们观察到体重和脂肪组织质量增加。在乳腺癌细胞中，SerRS的乙酰化和核转位被大大抑制。SerRS的过表达，特别是乙酰化模拟赖氨酸到谷氨酰胺突变体，显着抑制从头脂质合成，因此大大抑制乳腺癌细胞的增殖和乳腺癌异种移植物在小鼠中的生长。我们进一步确定HDAC 4和HDAC 5调节SerRS的乙酰化和核转位。因此，我们确定了一个SerRS介导的抑制途径，在葡萄糖诱导的脂质生物合成，这是失调的乳腺癌。
Abnormally enhanced de novo lipid biosynthesis has been increasingly realized to play crucial roles in the initiation and progression of varieties of cancers including breast cancer. However, the mechanisms underlying the dysregulation of lipid biosynthesis in breast cancer remain largely unknown. Here, we reported that seryl tRNA synthetase (SerRS), a key enzyme for protein biosynthesis, could translocate into the nucleus in a glucose-dependent manner to suppress key genes involved in the de novo lipid biosynthesis. In normal mammary gland epithelial cells glucose can promote the nuclear translocation of SerRS by increasing the acetylation of SerRS at lysine 323. In SerRS knock-in mice bearing acetylation-defective lysine to arginine mutation, we observed increased body weight and adipose tissue mass. In breast cancer cells the acetylation and nuclear translocation of SerRS are greatly inhibited. Overexpression of SerRS, in particularly the acetylation-mimetic lysine to glutamine mutant, dramatically inhibits the de novo lipid synthesis and hence greatly suppresses the proliferation of breast cancer cells and the growth of breast cancer xenografts in mice. We further identified that HDAC4 and HDAC5 regulated the acetylation and nuclear translocation of SerRS. Thus, we identified a SerRS-meditated inhibitory pathway in glucose-induced lipid biosynthesis, which is dysregulated in breast cancer.
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影响因子：
56.9
作者：
Choudhary, Chunaram;Kumar, Chanchal;Mann, Matthias
通讯作者：
Mann, Matthias
影响因子：
4.4
作者：
Ozdag, Hilal;Teschendorff, Andrew E.;Caldas, Carlos
通讯作者：
Caldas, Carlos
DOI：
10.1073/pnas.0403390101
发表时间：
2004-07-20
影响因子：
11.1
作者：
Menendez, JA;Vellon, L;Lupu, R
通讯作者：
Lupu, R
影响因子：
3.9
作者：
Brownsey, RW;Boone, AN;Lee, WM
通讯作者：
Lee, WM
影响因子：
6.5
作者：
Matyash, Vitali;Liebisch, Gerhard;Schwudke, Dominik
通讯作者：
Schwudke, Dominik