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)

Background: GATA3 is regulated both transcriptionally and post-translationally. GATA3 is important for the function of FOXP3 ϩ Treg cells.

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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.

BACKGROUND. The tumor suppressor gene PTEN is a major negative regulator of the PI3K/Akt cellular survival pathway. Overexpression of PTEN by adenoviral transfection increases doxorubicin‐induced apoptosis. Whereas doxorubicin‐induced apoptosis can be potentiated by the histone deacetylase (HDAC) inhibitor Trichostatin A (TSA), the mechanisms underlying this process remain unclear. The aim of this work was to investigate whether changes in PTEN expression are involved in TSA/doxorubicin‐induced apoptosis. METHODS. We treated 293 T cells with TSA and doxorubicin, detected apoptosis by using Hoechst 33342 staining, and examined changes of PTEN and Egr‐1 expression by quantitative real‐time polymerase chain reaction (PCR). Luciferase reporter assay was used to evaluate the promoter activity of PTEN and Western blot and enzyme‐linked immunosorbent assay (ELISA) were used to confirm changes in the expression of PTEN. The chromatin immunoprecipitation (ChIP) assay was performed to estimate the acetylation level of PTEN promoter. RESULTS. Doxorubicin‐induced apoptosis was enhanced by TSA, whereas small interfering RNA (siRNA) targeting PTEN inhibited TSA/doxorubicin‐induced apoptosis. Also, TSA promoted Egr‐1 expression, which is the main transcription factor of PTEN, and this resulted in up‐regulation of PTEN expression, which consequently potentiated apoptosis. Moreover, histone acetyltransferase p300 was able to synergistically activate PTEN transcription with Egr‐1, implicating the role of histone acetylation in the regulation of PTEN expression. CONCLUSIONS. TSA promoted doxorubicin‐induced apoptosis through a mechanism that involved the stimulation of Egr‐1 expression, acetylation of core histones at the PTEN promoter, and consequently induction of PTEN transcription. These findings provide a theoretical basis for the therapeutic application of combined treatment of TSA/doxorubicin for cancer. Cancer 2007. © 2007 American Cancer Society.

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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