PTEN activation through K163 acetylation by inhibiting HDAC6 contributes to tumour inhibition.
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.
Central Laboratory, Peking University School and Hospital of Stomatology, Beijing, China.|Department of Oral & Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing, China.
Z
Z
Meng
Central Laboratory, Peking University School and Hospital of Stomatology, Beijing, China.
L-F
LF
Jia
Central Laboratory, Peking University School and Hospital of Stomatology, Beijing, China.|Department of Oral & Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing, China.
Y-H
YH
Gan
D000107:Acetylation / Q000187:drug effects; D000818:Animals; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008239:Lysine / Q000378:metabolism*; D051379:Mice; D009361:Neoplasm Invasiveness; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects; D000077337:Vorinostat; D023041:Xenograft Model Antitumor Assays
D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C012589:trichostatin A; D000077337:Vorinostat; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases; D008239:Lysine