| More and more non-nuclear proteins have been identified by different acetylation proteomics studies, most of them are metabolic enzymes. This indicating that acetylation as a reversible post translational modification may play a key role in the regulation of cellular metabolism. As we know, the altered cancer cell-intrinsic metabolism is an essential hallmark of cancer. Here we investigated the acetylation regulation of a key metabolic enzyme and demonstrated a novel mechanism of tumor cell proliferation.GAPDH is an obligatory enzyme in glycolysis. Our work focuses on its acetylation regulation. First of all, we reported a novel acetylation site-lysine 254 and identified it as the main acetylation site of GAPDH. The acetylation increases GAPDH activity in response to glucose signal. Furthermore, we found the acetyltransferase PCAF increases the acetylation level of GAPDH and also up regulates its enzyme activity. In contrast, the deacetylase HDAC5 can deacetylate GAPDH and down regulate its activity. Both PCAF and HDAC5 can interact with GAPDH, and high glucose can enhance the interaction between PCAF and GAPDH but decrease the interaction between HDAC5 and GAPDH.We also found that the acetylation of K254 promotes the nuclear translocation of GAPDH. Under TSA, SFM and LY294002 treatment, GAPDH wild type can translocate to the nuclear but the mutants do not response to these signals.Last but not the least, we found substitution of K254 to glutamine compromises the ability of GAPDH to support both the cell proliferation in human A549 and the tumor growth in nude mice in vivo.This study demonstrated the critical role of acetylation regulation of GAPDH coordinating with glucose signal to promote cell growth and tumorigenesis, which not only reveals a mechanism of GAPDH enzyme activity regulation but also provides a potential therapeutic target for GAPDH over-expressed cancers and other related diseases. |
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