Ricolinostat (ACY-1215) suppresses proliferation and promotes apoptosis in esophageal squamous cell carcinoma via miR-30d/PI3K/AKT/mTOR and ERK pathways

Abstract

Ricolinostat (ACY-1215), a first-in-class selective HDAC6 inhibitor, exhibits antitumor effects alone or in combination with other drugs in various cancers. However, its efficacy in esophageal cancer remains unclear. In this study, we found that the high expression of HDAC6 was associated with poor prognosis in esophageal squamous cell carcinoma (ESCC) tissues. Then, we identified that ACY-1215 significantly inhibited cellular proliferation in ESCC, and caused G2/M phase arrest and apoptosis. We further demonstrated that ACY-1215 treatment reduced the expression of PI3K, P-AKT, P-mTOR, and P-ERK1/2 and increased that of Ac-H3K9 and Ac-H4K8. In addition, using miRNA microarray and bioinformatics analysis, we detected that ACY-1215 promoted miR-30d expression, and PI3K regulatory subunit 2 (PIK3R2) was a direct target of miR-30d. Anti-miR-30d partially rescued the G2/M phase arrest and apoptosis caused by ACY-1215 treatment. The reductions in PI3K, P-AKT, and P-mTOR expression were also partially reversed by miR-30d inhibitor. Furthermore, the effects of ACY-1215 inhibited ESCC proliferation were validated in a mouse xenograft model in vivo. In conclusion, our study showed that ACY-1215 suppressed proliferation and promoted apoptosis in ESCC via miR-30d/PI3K/AKT/mTOR and ERK pathways and that ACY-1215 may be a promising antitumor agent in ESCC.

E2F1 mediated DDX11 transcriptional activation promotes hepatocellular carcinoma progression through PI3K/AKT/mTOR pathway

“…For example, Wang et al reported that hydrogen sulfide activated PI3K/AKT/mTOR pathway to promote cancer progression in HCC 30 . In esophageal squamous cell carcinoma, ricolinostat (ACY-1215) could suppressed proliferation and promotes apoptosis via PI3K/AKT/mTOR pathway 31 . Moreover, studies by Wang et al demonstrated that PI3K/AKT/mTOR signaling pathway could promote autophagy of hepatocellular carcinoma cells regulated by Alpha-fetoprotein (AFP) 32 .…”

Emerging Role of Non-Coding RNAs in Esophageal Squamous Cell Carcinoma

“…MicroRNA-30d was observed to be upregulated which may be directly suppressing PI3K regulatory subunit 2 (PIK3R2). Additionally, the effects caused by PI3K/AKT signaling inhibition, apoptosis and cell cycle arrest have been reported to have been partially restored by anti-miRNA-30d [141]. Many such studies have been published so far, which reveal miRNAs as tumor suppressors or oncogenes (Table 1).…”

Novel HDAC6 selective inhibitors with 4-aminopiperidine-1- carboxamide as the core structure enhanced growth inhibitory activity of bortezomib in MCF-7 cells

“…Unfortunately, the poor pharmacokinetic properties limited its application. In contrast, another well-known HDAC6 selective inhibitor ACY-1215 has a rigid and less cumbersome capping group contributing to its HDAC6 selectivity; nevertheless, it exhibited a selectivity index of only about 10 against HDAC1-3 (21). We designed and synthesized a series of novel HDACis with the N-phenylpiperidine-1-carboxamide as the skeleton in this work.…”