Abstract
We previously showed that treating vascular endothelial cells with 3-methylcholanthrene (3MC) caused cell-cycle arrest in the Go/G1 phase; this resulted from the induction of p21 and p27 and a decreased level and activity of the cyclin-dependent kinase, Cdk2. We further investigated the molecular mechanisms that modulate cell-cycle regulatory proteins through the aryl-hydrocarbon receptor (AhR)/Ras homolog gene family, member A (RhoA) dependent epigenetic modification of histone. AhR/RhoA activation mediated by 3MC was essential for the upregulation of retinoblastoma 2 (pRb2) and histone deacetylase 1 (HDAC1), whereas their nuclear translocation was primarily modulated by RhoA activation. The combination of increased phosphatase and tensin homolog (PTEN) activity and decreased phosphatidylinositide 3-kinase (PI3K) activation by 3MC led to the inactivation of the Ras-cRaf pathway, which contributed to pRb2 hypophosphorylation. Increased HDAC1/pRb2 recruitment to the E2F1 complex decreased E2F1-transactivational activity and H3/H4 deacetylation, resulting in the downregulation of cell-cycle regulatory proteins (Cdk2/4 and Cyclin D3/E). Co-immunoprecipitation and electrophoretic mobility shift assay (EMSA) results showed that simvastatin prevented the 3MC-increased binding activities of E2F1 proteins in their promoter regions. Additionally, RhoA inhibitors (statins) reversed the effect of 3MC in inhibiting DNA synthesis by decreasing the nuclear translocation of pRb2/HDAC1, leading to a recovery of the levels of cell-cycle regulatory proteins. In summary, 3MC decreased cell proliferation by the epigenetic modification of histone through an AhR/RhoA-dependent mechanism that can be rescued by statins.
Highlights
Environmental contamination by polycyclic aromatic hydrocarbons, such as 2,3,7,8-tetrachlorodibenzodioxin, polychlorinated biphenyls, and 3-methylcholanthrene (3MC) adversely affects wildlife and human health
The results showed that siHDAC1 significantly reversed the 3MC-mediated H3/H4 deacetylation at 1 h in concomitant recovery in histone acetylation; at 6 h after treatment, the protein levels of Cdk2/4 and Cyclin D3/E were rescued by the histone deacetylase 1 (HDAC1) knockdown
In light of the dependence of RhoA activation in augmenting nuclear translocation of pRb2/HDAC1 to form an E2F1 complex in Mouse cerebral vascular endothelial cells (MCVECs) (Figure 3), we examined whether treatment with simvastatin, which is an inhibitor of RhoA activation, would prevent 3MC-mediated increases in the binding activities of E2F1 with the promoters of the target genes
Summary
Environmental contamination by polycyclic aromatic hydrocarbons, such as 2,3,7,8-tetrachlorodibenzodioxin, polychlorinated biphenyls, and 3-methylcholanthrene (3MC) adversely affects wildlife and human health. Biochemical and genetic studies have shown that the action of 2,3,7,8-tetrachlorodibenzodioxin (TCDD) and 3MC is mediated by aryl hydrocarbon receptors (AhRs). The AhR is a ligand-activated transcription factor and acts as the receptor for polycyclic aromatic hydrocarbons, polychlorinated biphenyls, and TCDD, which diffuses across plasma membranes and binds to the AhR complex present in the cytoplasmic compartment [1]. Ligand AhR complexes are translocated into the nucleus, where they interact with the nuclear aryl hydrocarbon receptor nuclear translocator (Arnt) protein. The cell cycle is mediated by the activation of cyclins and cyclindependent kinases (Cdks), proteins that jointly initiate progression from the G1 phase to the S phase of the cell cycle, and from the G2 phase to mitosis. Our previous study showed that treating human umbilical cord vascular endothelial cells (HUVECs) with 3MC increased the upregulation of p21 and p27 and decreased the level and activity of Cdk; these alterations resulted in cell-cycle arrest in the G0/ G1 phase [4]
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