ArticleCancers2022
HDAC2- and EZH2-Mediated Histone Modifications Induce PDK1 Expression through miR-148a Downregulation in Breast Cancer Progression and Adriamycin Resistance.
Article in Cancers, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 16 citations in OpenAlex.
- Redox-Guided Epigenetic Signaling in Cancer: miRNA-DNMT Feedback Loops as Epigenetic Memory Modulates.Antioxidants (Basel, Switzerland) · 2026Review
- Immune-Epigenetic Effects of Environmental Pollutants: Mechanisms, Biomarkers, and Transgenerational Impact.Current issues in molecular biology · 2025Review
- HDAC2 mediates the activation of macrophage in sepsis induced lung injury via regulating the acetylation of SOX2 and the transcription of STAMP2.European journal of medical research · 2025Article
- Targeting ncRNAs to overcome metabolic reprogramming‑mediated drug resistance in cancer (Review).International journal of oncology · 2025Review
- Targeting PDK1: A novel approach to combat hypoxia-induced epithelial-mesenchymal transition in chronic rhinosinusitis with nasal polyps.Clinical and translational allergy · 2025Article
- Molecular Insights into Phytochemicals Mediated Epigenetic Regulation in Preclinical Models of Breast Cancer.Drug design, development and therapy · 2025Review
- PDK1 promotes breast cancer progression by enhancing the stability and transcriptional activity of HIF-1α.Genes & diseases · 2024Article
- Apoptosis, a Metabolic "Head-to-Head" between Tumor and T Cells: Implications for Immunotherapy.Cells · 2024Review
- Article
- HDAC2 as a target for developing anti-cancer drugs.Computational and structural biotechnology journal · 2023Review
- MicroRNAs: A Link between Mammary Gland Development and Breast Cancer.International journal of molecular sciences · 2022Review
- The roles of histone modifications in tumorigenesis and associated inhibitors in cancer therapy.Journal of the National Cancer Center · 2022Review
- Clinical Significance of the Histone Deacetylase 2 (HDAC-2) Expression in Human Breast Cancer.Journal of personalized medicine · 2022Article
- Epigenetic alterations in canine mammary cancer.Genetics and molecular biology · 2022Article
Corrections and comments
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Authors and funding
7 authors at 4 institutions in 2 countries.
Funding
Abstract
backgroundBreast cancer has one of highest morbidity and mortality rates for women. Abnormalities regarding epigenetics modification and pyruvate dehydrogenase kinase 1 (PDK1)-induced unusual metabolism contribute to breast cancer progression and chemotherapy resistance. However, the role and mechanism of epigenetic change in regulating PDK1 in breast cancer remains to be elucidated.
methodsGene set enrichment analysis (GSEA) and Pearson's correlation analysis were performed to analyze the relationship between histone deacetylase 2 (HDAC2), enhancer of zeste homologue 2 (EZH2), and PDK1 in database and human breast cancer tissues. Dual luciferase reporters were used to test the regulation between PDK1 and miR-148a. HDAC2 and EZH2 were found to regulate miR-148a expression through Western blotting assays, qRT-PCR and co-immunoprecipitation assays. The effects of PDK1 and miR-148a in breast cancer were investigated by immunofluorescence (IF) assay, Transwell assay and flow cytometry assay. The roles of miR-148a/PDK1 in tumor growth were investigated in vivo.
resultsWe found that PDK1 expression was upregulated by epigenetic alterations mediated by HDAC2 and EZH2. At the post-transcriptional level, PDK1 was a new direct target of miR-148a and was upregulated in breast cancer cells due to miR-148a suppression. PDK1 overexpression partly reversed the biological function of miR-148a-including miR-148a's ability to increase cell sensitivity to Adriamycin (ADR) treatment-inhibiting cell glycolysis, invasion and epithelial-mesenchymal transition (EMT), and inducing apoptosis and repressing tumor growth. Furthermore, we identified a novel mechanism: DNMT1 directly bound to EZH2 and recruited EZH2 and HDAC2 complexes to the promoter region of miR-148a, leading to miR-148a downregulation. In breast cancer tissues, HDAC2 and EZH2 protein expression levels also were inversely correlated with levels of miR-148a expression.
conclusionOur study found a new regulatory mechanism in which EZH2 and HDAC2 mediate PDK1 upregulation by silencing miR-148a expression to regulate cancer development and Adriamycin resistance. These new findings suggest that the HDAC2/EZH2/miR-148a/PDK1 axis is a novel mechanism for regulating cancer development and is a potentially promising target for therapeutic options in the future.
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