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PTEN activation through K163 acetylation by inhibiting HDAC6 contributes to tumour inhibition

Oncogene volume 35, pages 2333–2344 (2016)Cite this article

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Abstract

Phosphatase and tensin homologue deleted on chromosome 10 (PTEN), an important tumour-suppressor gene, is mutated, downregulated or dysfunctional in many tumours. The phosphatase activity of PTEN depends on membrane translocation (activation). As promising anti-cancer agents, histone deacetylase (HDAC) inhibitors, particularly trichostatin A (TSA), can promote PTEN membrane translocation, but the underlying mechanism remains unknown. In this study, we revealed that non-selective HDAC inhibitors, namely, TSA or suberoylanilide hydroxamic acid (SAHA), induced PTEN membrane translocation through PTEN acetylation at K163 by inhibiting HDAC6. K163 acetylation inhibited the interaction of the PTEN C-tail with the remaining part of PTEN, resulting in PTEN membrane translocation. Overexpression of wild-type PTEN, but not K163-mutated PTEN, facilitated the inhibition of cell proliferation, migration and invasion, as well as xenograft tumour growth, induced by SAHA or tubastatin A, an HDAC6-specific inhibitor. These results indicated that PTEN activation by inhibiting HDAC6 significantly contributed to tumour inhibition. Therefore, non-selective HDAC or HDAC6-specific inhibitors may be more clinically suitable to treat tumours without PTEN mutations or deletions.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (Grant No. 81472764 and 81271173) and China International Science and Technology Cooperation (Grant No. 2013DFB30360).

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Authors and Affiliations

  1. Central Laboratory, Peking University School and Hospital of Stomatology, Beijing, China

    Z Meng, L-F Jia & Y-H Gan

  2. Department of Oral & Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing, China

    Z Meng & Y-H Gan

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Correspondence to Y-H Gan.

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Meng, Z., Jia, LF. & Gan, YH. PTEN activation through K163 acetylation by inhibiting HDAC6 contributes to tumour inhibition. Oncogene 35, 2333–2344 (2016). https://doi.org/10.1038/onc.2015.293

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