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 a recent study, researchers found that the high expression of HDAC6 was associated with poor prognosis in esophageal squamous cell carcinoma (ESCC) tissues.

Researchers subsequently identified that ACY-1215 significantly inhibited cellular proliferation in ESCC, and caused G2/M phase arrest and apoptosis. They 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, they 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, this 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.

The quantitative real-time PCR analysis demonstrated that PIK3R2 expression significantly increased after cells were transfected with miR-30d inhibitor, particularly in the ACY-1215 treatment group.