ArticleJournal of Cancer2021
Histone Deacetylase Inhibitor-Induced CDKN2B and CDKN2D Contribute to G2/M Cell Cycle Arrest Incurred by Oxidative Stress in Hepatocellular Carcinoma Cells via Forkhead Box M1 Suppression.
Article in Journal of Cancer, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 24 citations in OpenAlex.
- Unveiling Berberine's Therapeutic Mechanisms Against Hepatocellular Carcinoma via Integrated Computational Biology and Machine Learning Approaches: AURKA and CDK1 as Principal Targets.International journal of molecular sciences · 2025Article
- The oncogenic role of FOXM1 in hepatocellular carcinoma: molecular mechanisms, clinical significance, and therapeutic potentials.Naunyn-Schmiedeberg's archives of pharmacology · 2025Review
- GTF3C2 Promotes the Proliferation of Hepatocellular Carcinoma Cells through the USP21/MEK2/ERK1/2 Pathway.Journal of clinical and translational hepatology · 2025Article
- Article
- Synergistic Efficacy of CDK4/6 Inhibitor Abemaciclib and HDAC Inhibitor Panobinostat in Pancreatic Cancer Cells.Cancers · 2024Article
- Fragile X Messenger Ribonucleoprotein Protein and Its Multifunctionality: From Cytosol to Nucleolus and Back.Biomolecules · 2024Review
- N-acetylcysteine regulates oxalate induced injury of renal tubular epithelial cells through CDKN2B/TGF-β/SMAD axis.Urolithiasis · 2024Article
- 25(OH)D3 improves granulosa cell proliferation and IVF pregnancy outcomes in patients with endometriosis by increasing G2M+S phase cells.Reproductive biology and endocrinology : RB&E · 2023Article
- TWIST1 Upregulation Is a Potential Target for Reversing Resistance to the CDK4/6 Inhibitor in Metastatic Luminal Breast Cancer Cells.International journal of molecular sciences · 2023Article
- A systematic study on the treatment of hepatitis B-related hepatocellular carcinoma with drugs based on bioinformatics and key target reverse network pharmacology and experimental verification.Infectious agents and cancer · 2023Article
- BAIAP2L2 is a novel prognostic biomarker related to migration and invasion of HCC and associated with cuprotosis.Scientific reports · 2023Article
- LINC01012 upregulation promotes cervical cancer proliferation and migration via downregulation of CDKN2D.Oncology letters · 2023Article
- From imaging to clinical outcome: dual-region CT radiomics predicting FOXM1 expression and prognosis in hepatocellular carcinoma.Frontiers in oncology · 2023Article
- miR-199a-3p increases the anti-tumor activity of palbociclib in liver cancer models.Molecular therapy. Nucleic acids · 2022Article
- Molecular Mechanisms Related to Responses to Oxidative Stress and Antioxidative Therapies in COVID-19: A Systematic Review.Antioxidants (Basel, Switzerland) · 2022Review
- Construction of a Novel Oxidative Stress Response-Related Gene Signature for Predicting the Prognosis and Therapeutic Responses in Hepatocellular Carcinoma.Disease markers · 2022Article
- ERα and ERβ Homodimers in the Same Cellular Context Regulate Distinct Transcriptomes and Functions.Frontiers in endocrinology · 2022Article
- Insights Into the Properties, Biological Functions, and Regulation of USP21.Frontiers in pharmacology · 2022Review
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Forkhead box protein M1 (FOXM1) is a pivotal regulator of G2/M cell cycle progression in many types of cancer. Previously, our study demonstrated that histone deacetylase inhibition (HDACi) sensitizes hepatocellular carcinoma cells (HCC) to oxidative stress through FOXM1 suppression. However, the mechanism underlying its suppression by HDACi still requires elucidation. We hypothesized that HDACi induce genes responsible for destabilizing and inactivating FOXM1. The transcriptome in the HepG2 was revealed by massive analysis of cDNA end (MACE). Expression of mRNA and proteins were analyzed by quantitative real-time PCR (qPCR) and western blot, respectively. Cell cycle was analyzed by fluorescence-activated cell sorting (FACS). Oxidative stress and HDACi suppressed CDK4/6 levels while enhancing CDK inhibitor 2B and 2D (CDKN2B and CDKN2D) expressions in HCC. Palbociclib, a specific inhibitor of CDK4/6, induced G2/M cell cycle arrest in HCC by down-regulating phosphorylation level of FOXM1, and its downstream target genes such as aurora kinase A (AURKA) and polo-like kinase 1 (PLK1). HDACi treatment increased the ubiquitination level of FOXM1 by suppressing ubiquitin-specific peptidase 21 (USP21), which deubiquitinates FOXM1. Inhibiting FOXM1 degradation with MG132 treatment affected neither palbociclib-induced G2/M cell cycle arrest nor expression of its target genes. Double knockdown of CDKN2B and CDKN2D reduced the oxidative stress and HDACi-induced G/2M cell cycle arrest. In conclusion, oxidative stress and HDACi synergistically cause G2/M cell cycle arrest via CDKN2 induction, which sequentially inhibits CDK4/6, FOXM1, and its downstream target genes AURKA, PLK1, and CCNB1 phosphorylation in HCC.
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