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

• Published in: Oncogene 2016-05, Vol.35 (18), p.2333-2344
• Main Authors: Meng, Z, Jia, L-F, Gan, Y-H
• Format: Article
• Language: English
• Subjects: 38/109; 38/70; 38/77; 631/67/1059; 631/67/581; 82/1; 82/80; Acetylation; Acetylation - drug effects; Animals; Antitumor agents; Apoptosis; Cancer; Carcinogenesis; Cell adhesion & migration; Cell Biology; Cell Line, Tumor; Cell Membrane - drug effects; Cell Membrane - metabolism; Cell migration; Cell Movement - drug effects; Cell proliferation; Cell Proliferation - drug effects; Chromosome 10; Development and progression; Enzyme Activation - drug effects; Enzyme inhibitors; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Genetic aspects; Health aspects; Histone deacetylase; Histone Deacetylase 6; Histone Deacetylase Inhibitors - pharmacology; Histone Deacetylases - metabolism; Human Genetics; Humans; Hydroxamic acid; Hydroxamic Acids - pharmacology; Internal Medicine; Kinases; Lysine - metabolism; Medicine; Medicine & Public Health; Mice; Mutation; Neoplasm Invasiveness; Oncology; original-article; Patient outcomes; Phosphatase; Properties; Protein Transport - drug effects; PTEN Phosphohydrolase - metabolism; PTEN protein; Tensin; Translocation (Genetics); Trichostatin A; Tumor suppressor genes; Tumors; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2015.293

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.