Previous studies have shown an anticancer effect of vitamin D, but the mechanisms underlying this action have not been fully explored. Here we show that 1,25‐dihydroxyvitamin D3 (VD3, the active form of vitamin D) significantly promoted apoptosis in the undifferentiated gastric cancer cell line HGC‐27, and this was accompanied by a concurrent increase in phosphatase and tensin homolog deleted on chromosome 10 (PTEN) expression on VD3 treatment. In contrast, knockdown of PTEN expression by stable transfection of PTEN small interfering RNA greatly decreased the apoptosis rate. We further demonstrated that VD3 induced PTEN expression through vitamin D receptor. In addition, our evidence showed that vitamin D receptor, Egr‐1 and p300 induced PTEN expression in a synergistic fashion. Furthermore, we found that the histone deacetylase inhibitors trichostatin A and sodium butyrate and the methylation inhibitor 5‐aza‐2′‐deoxycytidine played important roles in vitamin D‐induced apoptosis through PTEN upregulation. The data presented in this article suggest potential benefits of vitamin D in gastric cancer therapies in association with the use of trichostatin A/sodium butyrate and 5‐aza‐2′‐deoxycytidine.
Structured digital abstract
http://mint.bio.uniroma2.it/mint/search/interaction.do?interactionAc=MINT-7306489, http://mint.bio.uniroma2.it/mint/search/interaction.do?interactionAc=MINT-7306501, http://mint.bio.uniroma2.it/mint/search/interaction.do?interactionAc=MINT-7306512: P300 (uniprotkb:http://www.uniprot.org/uniprot/Q09472?format=text&ascii) physically interacts (http://www.ebi.ac.uk/ontology-lookup/?termId=MI:0914) with VDR (uniprotkb:http://www.uniprot.org/uniprot/P11473?format=text&ascii) and EGR1 (uniprotkb:http://www.uniprot.org/uniprot/P18146?format=text&ascii) by anti bait coimmunoprecipitation (http://www.ebi.ac.uk/ontology-lookup/?termId=MI:0006)
As a cyclin-dependent kinase inhibitor, p16 INK4a plays a key role in cell cycle progression and cellular differentiation, and its expression is frequently altered in human cancers through epigenetically mediated transcriptional silencing. In this report, we demonstrate that p300 was able to induce cell cycle arrest, and this process was reversed by p16 INK4a silencing by RNA interference in HeLa cells. We also show that p300 was involved in activation of p16 INK4a expression in 293T cells. Specifically, p300 cooperated with Sp1 to stimulate both p16 INK4a promoter activity and mRNA expression. Co-immunoprecipitation and mammalian twohybrid assays revealed that p300 and Sp1 formed a complex through interaction between the Q domain of p300 and the N-terminal domain of Sp1. The chromatin immunoprecipitation assays verified that p300 was recruited to p16 INK4a promoter, and the histone acetyltransferase domain of p300 participated in p16 INK4a activation through inducing hyperacetylation of histone H4 at p16 INK4a gene. These data suggest that p300 plays a critical role in transcriptional regulation of p16 INK4a and in cell cycle arrest.
Increased glycolysis in tumor cells is associated with increased risk of tumor progression and mortality. Therefore, disruption of glycolysis, one of the main sources of cellular energy supply, can serve as a target for suppressing tumor growth and progression. Of note, hexokinase-2 (HK2) plays vital roles in glucose metabolism. Moreover, the expression of HK2 alters the metabolic phenotype and supports the continuous growth of tumor cells, making it an attractive target for cancer therapy. Quercetin (QUE), a bioactive flavonoid, has a profound anti-tumor effect on hepatocellular carcinoma (HCC), but the precise underlying mechanism of this effect is unclear. In the present study, we reported that QUE inhibited the proliferation of HCC cells that relied on aerobic glycolysis. We further found that QUE could decrease the protein levels of HK2 and suppress the AKT/mTOR pathway in HCC cells. In addition, QUE significantly restrained the growth of HCC xenografts and decreased HK-2 expression in vivo. Taken together, we have revealed that QUE suppresses the progression of HCC by inhibiting HK2-dependentglycolysis, which may have a promising potential to be an effective treatments for HCC, especially for those patients with high HK2 expression.
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