HDAC2‐Mediated SMAD7 Stabilisation Activates Wnt/β‐Catenin Signalling to Drive DNA Damage Repair and Cisplatin Resistance in Ovarian Cancer
TL;DR
Overexpression of HDAC2 enhanced drug resistance and inhibited apoptosis and DNA damage, whereas knockdown of HDAC2 exhibited the opposite effects; in vivo experiments confirmed that HDAC2 knockdown significantly inhibited tumour growth and enhanced the sensitivity.
Abstract
To investigate the role of histone deacetylase 2 (HDAC2) in cisplatin resistance in ovarian cancer (OC). Cisplatin‐resistant OC cell lines were employed to construct HDAC2 overexpression and knockdown models, and their effects on cell proliferation and apoptosis were examined. Chromatin immunoprecipitation, immunoprecipitation, and dual‐luciferase reporter assays were performed to investigate the regulation of SMAD7 protein stability and promoter activity by HDAC2. Expression of DNA damage repair‐related genes was detected by qRT‐PCR. A xenograft mouse model was established for in vivo validation. HDAC2 was highly expressed in cisplatin‐resistant OC cells. Overexpression of HDAC2 enhanced drug resistance and inhibited apoptosis and DNA damage, whereas knockdown of HDAC2 exhibited the opposite effects. Mechanistically, HDAC2 directly deacetylated the SMAD7 protein to prevent its degradation rather than suppressing its transcription via H3K27 deacetylation. The HDAC2/SMAD7 axis promoted drug resistance by activating the Wnt/β‐catenin signalling pathway and modulating DNA damage repair‐related genes. In vivo experiments confirmed that HDAC2 knockdown significantly inhibited tumour growth and enhanced the sensitivity. HDAC2 enhances cisplatin resistance in OC by deacetylating and stabilising SMAD7 protein, thereby activating the Wnt/β‐catenin signalling pathway and promoting DNA damage repair.