HDAC inhibitor DWP0016 suppresses miR-22 to induce growth inhibition and apoptosis via p53-independent PTEN activation in neuroblastoma SH-SY5Y cells

Here we report a histone deacetylase (HDAC) inhibitor named DWP0016, which exhibits anti-neuroblastoma potential in vitro. DWP0016 effectively inhibited proliferation of neuroblastoma SH-SY5Y cells at submicromolar levels but did not affect the growth of normal cells. Flowcytometry analysis showed DWP0016 arrested cell cycle at G1 phase and induced apoptosis in SH-SY5Y cells dose-dependently. Western-blotting results showed DWP0016 induced significant increase of histone H3 acetylation in neuroblastoma SH-SY5Y cells. Molecular mechanistic studies suggested that DWP0016 activated p21Cip/WAF1, p27/KIP1 and caspase-3, -9 which facilitated to contribute the cell cycle and apoptosis. Besides, DWP0016 activated tumor suppressor PTEN to inhibit the PI3K/Akt cell signal pathway. Intensive investigations showed down-regulation of miR-22 by DWP0016 stimulated the activity of PTEN promoter and then enhanced PTEN at both transcription and protein expression level. SiRNA silencing results suggested knockdown of PTEN sufficiently blocked cell growth inhibition, cell cycle arrest and apoptosis induced by DWP0016 in SH-SY5Y cells. Conclusively, our results showed DWP0016 was a promising candidate for neuroblastoma treatment with its PTEN and microRNA regulations mechanisms.