Abstract
Background and purposeHistone deacetylase (HDAC) inhibitors (HDIs) can modulate the epithelial-mesenchymal transition (EMT) progression and inhibit the migration and invasion of cancer cells. Emerging as a novel class of anti-cancer drugs, HDIs are attracted much attention in the field of drug discovery. This study aimed to discern the underlying mechanisms of Honokiol in preventing the metastatic dissemination of gastric cancer cells by inhibiting HDAC3 activity/expression.Experimental approachClinical pathological analysis was performed to determine the relationship between HDAC3 and tumor progression. The effects of Honokiol on pharmacological characterization, functional, transcriptional activities, organelle structure changes, and molecular signaling were analyzed using binding assays, differential scanning calorimetry, luciferase reporter assay, HDAC3 activity, ER stress response element activity, transmission electron microscopy, immune-blotting, and Wnt/β-catenin activity assays. The in vivo effects of Honokiol on peritoneal dissemination were determined by a mouse model and detected by PET/CT tomography.Key resultsHDAC3 over-expression was correlated with poor prognosis. Honokiol significantly abolished HDAC3 activity (Y298) via inhibition of NFκBp65/CEBPβ signaling, which could be reversed by the over-expression of plasmids of NFκBp65/CEBPβ. Treatments with 4-phenylbutyric acid (a chemical chaperone) and calpain-2 gene silencing inhibited Honokiol-inhibited NFκBp65/CEBPβ activation. Honokiol increased ER stress markers and inhibited EMT-associated epithelial markers, but decreased Wnt/β-catenin activity. Suppression of HDAC3 by both Honokiol and HDAC3 gene silencing decreased cell migration and invasion in vitro and metastasis in vivo.Conclusions and implicationsHonokiol acts by suppressing HDAC3-mediated EMT and metastatic signaling. By prohibiting HDAC3, metastatic dissemination of gastric cancer may be blocked.Graphical abstractConceptual model showing the working hypothesis on the interaction among Honokiol, HDAC3, and ER stress in the peritoneal dissemination of gastric cancer. Honokiol targeting HDAC3 by ER stress cascade and mitigating the peritoneal spread of gastric cancer. Honokiol-induced ER stress–activated calpain activity targeted HDAC3 and blocked Tyr298 phosphorylation, subsequently blocked cooperating with EMT transcription factors and cancer progression. The present study provides evidence to demonstrate that HDAC3 is a positive regulator of EMT and metastatic growth of gastric cancer cells. The findings here imply that overexpressed HDAC3 is a potential therapeutic target for honokiol to reverse EMT and prevent gastric cancer migration, invasion, and metastatic dissemination.• Honokiol significantly abolished HDAC3 activity on catalytic tyrosine 298 residue site. In addition, Honokiol-induced ER stress markedly inhibited HDAC3 expression via inhibition of NFκBp65/CEBPβ signaling.• HDAC3, which is a positive regulator of metastatic gastric cancer cell growth, can be significantly inhibited by Honokiol.• Opportunities for HDAC3 inhibition may be a potential therapeutic target for preventing gastric cancer metastatic dissemination.
Highlights
The incidence and mortality of cancers, including gastric cancer, are linked with tumor progression, from localized primary tumors to more advanced stages that metastasize and involve multiple organs (Brabletz 2012; Gherardi et al 2012; Williams et al 2019)
Honokiol acts by suppressing HDAC3-mediated epithelial mesenchymal transition (EMT) and metastatic signaling
The percentage of positive tumor cells and staining intensity for each sample were recorded. These results indicated that the level of HDAC3 expression closely correlated with increased clinical stage, as well as with lymph node and distant metastasis of the tumor-node-metastasis (TNM) classification
Summary
The incidence and mortality of cancers, including gastric cancer, are linked with tumor progression, from localized primary tumors to more advanced stages that metastasize and involve multiple organs (Brabletz 2012; Gherardi et al 2012; Williams et al 2019). In cancers of the gastrointestinal tract, the peritoneum is the primary site of metastasis. The spread is associated with the loss of epithelial characteristics and the acquisition of a mesenchymal phenotype, leading to invasion and metastasis (Brabletz et al 2018). Gastric cancer is the second leading cause of cancer-related deaths globally (GBD 2017 Stomach Cancer Collaborators 2020). Most patients will relapse or have local recurrence after definitive surgical treatment. What is the clinical significance HDAC3, which is a positive regulator of metastatic gastric cancer cell growth, can be significantly inhibited by Honokiol. Opportunities for HDAC3 inhibition may be a potential therapeutic target for preventing gastric cancer metastatic dissemination
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