Plant Isoquinoline Alkaloid Berberine Exhibits Chromatin Remodeling by Modulation of Histone Deacetylase To Induce Growth Arrest and Apoptosis in the A549 Cell Line

Abstract

Histone deacetylases (HDACs) are a group of epigenetic enzymes that control gene expression through their repressive influence on histone deacetylation transcription. HDACs are probable therapeutic targets for cancer treatment, spurring the progress of different types of HDAC inhibitors. Further, natural-source-based derived bioactive compounds possess HDAC inhibitor property. In this way, we hypothesized that plant isoquinoline alkaloid berberine (BBR) could be a HDAC inhibitor in the human lung cancer A549 cell line. BBR represses total HDAC and also class I, II, and IV HDAC activity through hyperacetylation of histones. Furthermore, BBR triggers positive regulation of the sub-G/G cell cycle progression phase in A549 cells. Moreover, BBR-induced A549 cell growth arrest and morphological changes were confirmed using different fluorescence-dye-based microscope techniques. Additionally, BBR downregulates oncogenes (TNF-α, COX-2, MMP-2, and MMP-9) and upregulates tumor suppressor genes (p21 and p53) mRNA and protein expressions. Besides, BBR actively regulates Bcl-2/Bax family proteins and also triggered the caspase cascade apoptotic pathway in A549 cells. Our finding suggests that BBR mediates epigenetic reprogramming by HDAC inhibition, which may be the key mechanism for its antineoplastic activity.

Traditional Chinese medicine as a cancer treatment: Modern perspectives of ancient but advanced science

“…In colon tumor cells, berberine treatment was demonstrated to suppress EGFR expression via enhancement of Cbl activity . As for the regulation of apoptosis regulators, curcumin, resveratrol, and berberine have all been shown to trigger apoptosis and increase the ratio of Bax/Bcl‐2 expression . In fact, apoptosis has wide involvement in the antitumor effects of treating with CHM.…”

“…p53 acetylation and so activation occurs as a result of resveratrol's role in the inhibition of MTA1 that leads to increased p53 acetylation . Additionally, berberine has been shown to repress total HDAC but specifically class I, II, and IV HDAC activity via hyperacetylation of histones, downregulation of oncogene expression (TNF‐α, COX‐2, MMP‐2, and MMP‐9), and upregulation of the expression of tumor suppressor genes (p21 and p53) . It appears that histone acetylation and deacetylation have broad involvement in cancer treatment using TCM.…”

“…DNMT1, DNMT3B↓; CREBBP, EP300, SIRT3, KDM6A, SETD7↑; HDAC8, H3K4me3, H3K27me3, H3K36me3↓; pan‐HDAC inhibitor …”

Abilities of berberine and chemically modified berberines to interact with metformin and inhibit proliferation of pancreatic cancer cells

“…This resulted in decreases in prostaglandin-endoperoxide synthase 2 (COX2), matrix metalloproteinase (MMP2), MMP9 and tumor necrosis factor-alpha (TNF-α) expression and increases in TP53 and p21 Cip−1 levels. BBR was determined to regulate apoptotic activity (Kalaiarasi et al, 2016). In this system, BBR could have both direct and indirect effects on DNA by altering chromatin structure and TP53 expression.…”

The Roles of Natural Compounds in Epigenetics

“…Natural Product Communications Vol. 13 (8) 2018 1069 Berberine can act as a HDAC inhibitor, and it inhibits HDAC activity via acetylation of histones in lung cancer A549 cells [49]. SIRT1 is essential for berberine to potentiate autophagy and inhibit lipid storage in mouse livers in response to fasting; berberine stimulates SIRT1 deacetylation activity and induces autophagy in an Atg5-dependent manner [50].…”