HDAC2-mediated H3K27 acetylation promotes the proliferation and migration of hepatocellular carcinoma cells.
- Author:
Shaohai TANG
1
;
Baoming YANG
1
;
Jiankun LI
1
;
Lili ZHAO
2
;
Yifan WANG
3
;
Shunxiang WANG
1
Author Information
1. Department of Hepatobiliary Surgery, the Fourth Hospital of Hebei Medical University, Shijiazhuang 050000, China.
2. College of Pharmacy, Hebei Medical University, Shijiazhuang 050000, China.
3. Department of Colorectal Surgery, the Fourth Hospital of Hebei Medical University, Shijiazhuang 050000, China.
- Publication Type:Journal Article
- Keywords:
Hepatocellular carcinoma;
Histone H3 lysine 27 acetylation;
Histone deacetylase 2;
Migration;
Proliferation
- MeSH:
Humans;
Carcinoma, Hepatocellular/metabolism*;
Liver Neoplasms/metabolism*;
Histone Deacetylase 2/physiology*;
Cell Proliferation;
Acetylation;
Cell Movement;
Histones/metabolism*;
Animals;
Hep G2 Cells;
Male;
Female;
Mice;
Cell Line, Tumor;
Signal Transduction;
Mice, Nude;
PTEN Phosphohydrolase/metabolism*;
Lysine/metabolism*;
Middle Aged
- From:
Journal of Peking University(Health Sciences)
2025;57(5):884-894
- CountryChina
- Language:Chinese
-
Abstract:
OBJECTIVE:To explore the specific mechanism of histone deacetylase 2 (HDAC2) mediated histone H3 lysine 27 acetylation (H3K27ac) modification in promoting the proliferation and migration of hepatocellular carcinoma cells.
METHODS:Samples of 40 cases of hepatocellular carcinoma and paracancerous tissues resected from January 2021 to January 2023 were collected. The expressions of HDAC2 and H3K27ac in hepatocellular carcinoma, paracancerous tissues and cell lines were detected by immunohistochemistry and Western blotting. The correlation between the expression levels of HDAC2 and H3K27ac and the relationship between HDAC2 expression and clinicopathological characteristics of patients with hepatocellular carcinoma were analyzed. The proliferation, migration and invasion of Hep3B and HepG2 cells were determined by MTS, clone formation, scratch and Transwell experiments. The acetylation of H3K27 mediated by HDAC2 was verified by Western blotting, real-time fluorescence quantitative PCR (qRT-PCR) and chromatin immunoprecipitation high-throughput sequencing (ChIP-seq). In vivo xenotransplantation experiment, the tumorigenicity of cells in each group was measured, and the expression of proteins related to phosphoinositide 3-kinases/phosphatase and tensin homolog deleted on chromosome ten/protein kinase B/mammalian target of rapamycin (PI3K/PTEN/AKT/mTOR) signal pathway was detected.
RESULTS:High expression of HDAC2 and low expression of H3K27ac were found in hepatocellular carcinoma tissues and cell lines (P < 0.05), and there was a negative correlation between them (r=-0.477, P=0.002). The expression of HDAC2 was related to tumor size, hepatitis B virus infection, TNM stage and portal vein tumor thrombus (P < 0.05). Compared with the sh-NC group of Hep3B and HepG2 cells, the proliferation, clone formation, migration and invasion ability of sh-HDAC2 group were decreased (P < 0.05). Compared with the Empty group, the HDAC2 group exhibited increased expression levels and activity of HDAC2, as well as enhanced cell proliferation, clone formation, migration, invasion ability, tumor volume and mass in vivo, and elevated expression levels of p-PI3K, p-AKT, and p-mTOR (P < 0.05). Conversely, the enrichment and expression levels of H3K27ac, along with the expression level of PTEN, were decreased (P < 0.05). In the iHDAC2 group, the expression levels and activity of HDAC2, as well as the proliferation, clone formation, migration, invasion ability, tumor volume and mass in vivo, and expression levels of p-PI3K, p-AKT, and p-mTOR were reduced (P < 0.05). Additionally, the expression levels of H3K27ac and PTEN were increased (P < 0.05). To validate the involvement of the PI3K/PTEN/AKT/mTOR signaling pathway in HDAC2-mediated regulation of malignant behaviors in liver cancer cells through H3K27ac, the PI3K activator 740Y-P was introduced. Compared with the iHDAC2 group, the iHDAC2+740Y-P group exhibited increased proliferation, clone formation, migration, invasion ability, tumor volume and mass in vivo, and elevated expression levels of p-PI3K, p-AKT, and p-mTOR (P < 0.05). Conversely, the expression level of PTEN was decreased (P < 0.05).
CONCLUSION:HDAC2 initiates PI3K/PTEN/AKT/mTOR signal pathway by mediating H3K27 acetylation, which promotes the occurrence and development of hepatocellular carcinoma.
