Abstract
The mechanistic action of histone deacetylase 8 (HDAC8) in cancer motility, including epithelial-mesenchymal transition (EMT), remains largely undefined. We found that the expression of HDAC8 was upregulated in breast cancer (BC) cells and tissues as compared to the controls. Further, BC tissues had the highest values of HDAC8 expression among 31 kinds of cancers. Cellular study indicated that HDAC8 can positively regulate the dissemination and EMT of BC cells. It increased the protein stability of Snail, an important regulator of EMT, by phosphorylation of its motif 2 in serine-rich regions. There are 21 factors that have been reported to regulate the protein stability of Snail. Among them, HDAC8 can decrease the expression of GSK-3β through increasing its Ser9-phosphorylation. Mass spectrum analysis indicated that HDAC8 interact with AKT1 to decrease its acetylation while increase its phosphorylation, which further increased Ser9-phosphorylation of GSK-3β. The C-terminal of AKT1 was responsible for the interaction between HDAC8 and AKT1. Further, Lys426 was the key residue for HDAC8-regulated deacetylation of AKT1. Moreover, HDAC8/Snail axis acted as adverse prognosis factors for in vivo progression and overall survival (OS) rate of BC patients. Collectively, we found that HDAC8 can trigger the dissemination of BC cells via AKT/GSK-3β/Snail signals, which imposed that inhibition of HDAC8 is a potential approach for BC treatment.
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Acknowledgements
We thank Dr Feng Liu and Prof Junjiu Huang at School of Life Sciences, Sun Yat-sen University for technical supports.
Funding
This research was supported by the National Natural Science Foundation of China (Grant Nos. 81973343, 81673454, 81672608, and 31801197), the Fundamental Research Funds for the Central Universities (Sun Yat-sen University) (19ykzd24, 19ykpy130), the Guangdong Provincial Key Laboratory of Construction Foundation (No. 2017B030314030), the Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery (2019B030301005), and the Natural Science Foundation of Guangdong Province (No. 2020A1515010291).
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Conception and design: ZC, HW; Acquisition of data: PA, YP, YL, ZL, FC, JL; Analysis and interpretation of data: PA, FC, JL, HZ, ZC; Writing, review, and/or revision of the manuscript: HW, ZC, YP.
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An, P., Chen, F., Li, Z. et al. HDAC8 promotes the dissemination of breast cancer cells via AKT/GSK-3β/Snail signals. Oncogene 39, 4956–4969 (2020). https://doi.org/10.1038/s41388-020-1337-x
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DOI: https://doi.org/10.1038/s41388-020-1337-x
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