Abstract
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.
Highlights
By using chromatin immunoprecipitation followed by DNA deepsequencing (ChIP-Seq) and transcriptome analysis, we identified many seryl tRNA synthetase (SerRS)-regulated genes involved in the de novo lipid biosynthesis
Glucose regulates the nuclear translocation of SerRS by acetylation which is dysregulated in breast cancer cells the nuclear translocation of SerRS and its significance in vascular development have been demonstrated in zebrafish,[21,22] our recent study showed that SerRS was able to promote telomere shortening and trigger the senescence of tumor cells,[23] suggesting an important role of nuclear SerRS against tumor development
In breast cancer cells MDA-MB-231, SerRS is mainly localized in the cytoplasm and its nuclear import cannot be promoted by glucose, glutamine, serine and acetate at all
Summary
In the de novo fatty acid (FA) biosynthesis, has been demonstrated in many types of tumors even in the presence of exogenous lipid sources, which plays essential roles in tumor development, progression and drug resistance by generating a diverse intracellular lipid pool for the synthesis of biological membranes, energy storage and the production of important signaling molecules.[1,2,3,4,5,6] Increased uptake of glucose and glutamine in cancer cells contributes the carbon source for the production of citrate, which is converted to acetylCoA by ATP-citrate lyase (ACLY) and subsequently carboxylated to malonyl-CoA by acetyl-CoA carboxylases (ACACs, known as ACCs), the rate-limiting step committing acetyl-CoA to FA biosynthesis.[7,8,9] seven malonyl-CoA molecules are condensed by fatty acid synthase (FASN) to generate palmitate (FA 16:0), which can be further elongated or desaturated to form other FA species.
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