Silencing of histone deacetylase 3 suppresses the development of esophageal squamous cell carcinoma through regulation of miR-494-mediated TGIF1

• Published in: Cancer cell international Vol. 22; no. 1; p. 191
• Main Authors: Yang, Yang, Zhang, Yuan, Lin, Zongxiang, Wu, Kai, He, Zhanfeng, Zhu, Dengyan, Zhao, Jia, Zhang, Chunyang, Fan, Yuxia
• Format: Journal Article
• Language: English
• Published: England BioMed Central 16-05-2022; BMC
• Subjects: Antibodies; Apoptosis; Bioinformatics; Biotechnology; Cancer therapies; Chemotherapy; Chromatin; Deacetylation; DNA damage; Esophageal cancer; Esophageal squamous cell carcinoma; Gene expression; Histone deacetylase; Histone deacetylase 3; Immunohistochemistry; Immunoprecipitation; Laboratory animals; microRNA-494; MicroRNAs; miRNA; Phenotypes; Primary Research; Proteins; Radiation therapy; Reporter gene; Signal transduction; Squamous cell carcinoma; Thoracic surgery; Transforming growth factor beta-inducing factor 1; Transforming growth factor-b; Transforming growth factor-β signaling pathway; Beijing China; United States > US; China; Esophageal squamous cell carcinoma; Transforming growth factor beta-inducing factor 1; Transforming growth factor-β signaling pathway; Histone deacetylase 3; microRNA-494
• ISSN: 1475-2867; 1475-2867
• DOI: 10.1186/s12935-022-02581-3

Deacetylation of histones by histone deacetylase 3 (HDAC3) acts importantly in modulating apoptosis, DNA damage and cellular progression. Herein, we aimed to unravel the functional role of HDAC3 in a lethal disease, esophageal squamous cell carcinoma (ESCC).
The expression of HDAC3 in clinically collected ESCC tissues was determined by RT-qPCR and immunohistochemistry. As revealed from bioinformatics analysis, the putative relations between HDAC3 and microRNA-494 (miR-494) and between miR-494 and transforming growth factor beta (TGFβ)-inducing factor 1 (TGIF1) were further verified by chromatin immunoprecipitation and dual-luciferase reporter gene assay. Functional roles of shRNA-mediated depletion of HDAC3, miR-494 mimic and overexpressed TGIF1 were explored by gain- and loss-of-function assays with regard to ESCC cell biological behaviors. A nude mouse model of ESCC was developed for in vivo validation.
HDAC3 was highly expressed in ESCC tissues, suggestive of poor prognosis while TGIF1 was upregulated and miR-494 was downregulated. Mechanistic investigation revealed that HDAC3 inhibited miR-494 expression and TGIF1 was a direct target of miR-494. Furthermore, silencing HDAC3 or overexpressing miR-494 was demonstrated to suppress aggressive phenotypes of ESCC cells both in vitro through the activated TGFβ signaling pathway and in vivo, while TGIF1 overexpression induced opposite results.
Collectively, our findings provided demonstration regarding the oncogenic property of HDAC3 in ESCC via the miR-494/TGIF1/TGFβ axis.