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Environ Toxicol. 2017 Feb;32(2):434-444. doi: 10.1002/tox.22247. Epub 2016 Feb 12.

Inhibition of MDA-MB-231 breast cancer cell proliferation and tumor growth by apigenin through induction of G2/M arrest and histone H3 acetylation-mediated p21WAF1/CIP1 expression.

Author information

1
Department of Medical Applied Chemistry, Chung Shan Medical University, Taichung, Taiwan.
2
Department of Medical Education, Chung Shan Medical University Hospital, Taichung, Taiwan.
3
Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
4
Department of Medical Education and Research, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
5
Department of Pathology, Chung Shan Medical University Hospital, Taichung, Taiwan.
6
Department of Urology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
7
Division of Hematology and Medical Oncology, Department of Internal Medicine, Taipei Medical University, Wan Fang Hospital, Taipei, Taiwan.
8
Genomics Research Center, Academia Sinica, Taipei, Taiwan.
9
Institute of Biochemical Science, College of Life Science, National Taiwan University, Taipei, Taiwan.
10
Department of Urology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.

Abstract

Apigenin (4',5,7-trihydroxyflavone), a flavonoid commonly found in fruits and vegetables, has anticancer properties in various malignant cancer cells. However, the molecular basis of the anticancer effect remains to be elucidated. In this study, we investigated the cellular mechanisms underlying the induction of cell cycle arrest by apigenin. Our results showed that apigenin at the nonapoptotic induction concentration inhibited cell proliferation and induced cell cycle arrest at the G2/M phase in the MDA-MB-231 breast cancer cell line. Immunoblot analysis indicated that apigenin suppressed the expression of cyclin A, cyclin B, and cyclin-dependent kinase-1 (CDK1), which control the G2-to-M phase transition in the cell cycle. In addition, apigenin upregulated p21WAF1/CIP1 and increased the interaction of p21WAF1/CIP1 with proliferating cell nuclear antigen (PCNA), which inhibits cell cycle progression. Furthermore, apigenin significantly inhibited histone deacetylase (HDAC) activity and induced histone H3 acetylation. The subsequent chromatin immunoprecipitation (ChIP) assay indicated that apigenin increased acetylation of histone H3 in the p21WAF1/CIP1 promoter region, resulting in the increase of p21WAF1/CIP1 transcription. In a tumor xenograft model, apigenin effectively delayed tumor growth. In these apigenin-treated tumors, we also observed reductions in the levels of cyclin A and cyclin B and increases in the levels of p21WAF1/CIP1 and acetylated histone H3. These findings demonstrate for the first time that apigenin can be used in breast cancer prevention and treatment through epigenetic regulation.

KEYWORDS:

apigenin; breast cancer; cell cycle arrest; histone H3 acetylation; p21WAF1/CIP1

PMID:
26872304
DOI:
10.1002/tox.22247
[Indexed for MEDLINE]

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