Worker and queen bees are genetically indistinguishable. However, queen bees are fertile, larger and have a longer lifespan than their female worker counterparts. Differential feeding of larvae with royal jelly controls this caste switching. There is emerging evidence that the queen-bee phenotype is driven by epigenetic mechanisms. In this study, we show that royal jelly-the secretion produced by the hypopharyngeal and mandibular glands of worker bees-has histone deacetylase inhibitor (HDACi) activity. A fatty acid, (E)-10-hydroxy-2-decenoic acid (10HDA), which accounts for up to 5% of royal jelly, harbours this HDACi activity. Furthermore, 10HDA can reactivate the expression of epigenetically silenced genes in mammalian cells. Thus, the epigenetic regulation of queen-bee development is probably driven, in part, by HDACi activity in royal jelly.

We previously reported that apicidin arrested human cancer cell growth through selective induction of p21 WAF1/Cip1 . In this study, the apoptotic potential of apicidin and its mechanism in HL60 cells was investigated. Treatment of HL60 cells with apicidin caused a decrease in viable cell number in a dose-dependent manner and an increase in DNA fragmentation, nuclear morphological change, and apoptotic body formation, concomitant with progressive accumulation of hyperacetylated histone H4. In addition, apicidin converted the procaspase-3 form to catalytically active effector protease, resulting in subsequent cleavages of poly-(ADP-ribose) polymerase and p21 WAF1/Cip1 . Incubation of HL60 cells with z-DEVD-fmk, a caspase-3 inhibitor, almost completely abrogated apicidin-induced activation of caspase-3, DNA fragmentation, and cleavages of poly-(ADP-ribose) polymerase and p21 WAF1/Cip1 . Moreover, these effects were preceded by an increase in translocation of Bax into the mitochondria, resulting in the release of cytochrome c and cleavage of procaspase-9. The addition of cycloheximide greatly inhibited activation of caspase-3 by apicidin by interfering with cleavage of procaspase-3 and DNA fragmentation, suggesting that apicidin-induced apoptosis was dependent on de novo protein synthesis. Consistent with these results, apicidin transiently increased the expressions of both Fas and Fas ligand. Preincubation with NOK-1 monoclonal antibody, which prevents the Fas-Fas ligand interaction and is inhibitory to Fas signaling, interfered with apicidin-induced translocation of Bax, cytochrome c release, cleavage of procaspase-3, and DNA fragmentation. Taken together, the results suggest that apicidin might induce apoptosis through selective induction of Fas/Fas ligand, resulting in the release of cytochrome c from the mitochondria to the cytosol and subsequent activation of caspase-9 and caspase-3.

A growing number of studies have demonstrated that physiological factors can influence the progression of several cancers via cellular immune function, angiogenesis and metastasis. Recently, stress-induced catecholamines have been shown to increase the expression of various cancer progressive factors, including vascular endothelial growth factor (VEGF), matrix metalloproteinases and interleukins. However, a detailed mechanism remains to be identified. In this study, we investigated the role of adrenergic receptors and hypoxia-inducible factor (HIF)-1a protein in catecholamine-induced VEGF expression and angiogenesis. Treatment of the cells with norepinephrine (NE) or isoproterenol induced VEGF expression and HIF-1a protein amount in a dose-dependent manner. Induction of VEGF expression by NE was abrogated when the cells were transfected with HIF-1a-specific siRNA. Similarly, adenylate cyclase activator forskolin and cyclic AMP-dependent protein kinase A inhibitor H-89 enhanced and decreased HIF-1a protein amount, respectively. More importantly, conditioned medium of NE-stimulated cancer cells induced angiogenesis in a HIF-1a protein-dependent manner. In addition, pretreatment of cells with propranolol, a b-adrenergic receptor (AR) blocker, completely abolished induction of VEGF expression and HIF-1a protein amount by NE in all of the tested cancer cells. However, treatment with the a1-AR blocker prazosin inhibited NE-induced HIF-1a protein amount and angiogenesis in SK-Hep1 and PC-3 but not MDA-MB-231 cells. Collectively, our results suggest that ARs and HIF-1a protein have critical roles in NE-induced VEGF expression in cancer cells, leading to stimulation of angiogenesis. These findings will help to understand the mechanism of cancer progression by stress-induced catecholamines and design therapeutic strategies for cancer angiogenesis.Researchers have shown that stress and other behavioral conditions are involved in cancer progression.

Protein methylation, a post-translational modification (PTM), is observed in a wide variety of cell types from prokaryotes to eukaryotes. With recent and rapid advancements in epigenetic research, the importance of protein methylation has been highlighted. The methylation of histone proteins that contributes to the epigenetic histone code is not only dynamic but is also finely controlled by histone methyltransferases and demethylases, which are essential for the transcriptional regulation of genes. In addition, many nonhistone proteins are methylated, and these modifications govern a variety of cellular functions, including RNA processing, translation, signal transduction, DNA damage response, and the cell cycle. Recently, the importance of protein arginine methylation, especially in cell cycle regulation and DNA repair processes, has been noted. Since the dysregulation of protein arginine methylation is closely associated with cancer development, protein arginine methyltransferases (PRMTs) have garnered significant interest as novel targets for anticancer drug development. Indeed, several PRMT inhibitors are in phase 1/2 clinical trials. In this review, we discuss the biological functions of PRMTs in cancer and the current development status of PRMT inhibitors in cancer therapy.

We previously reported that apicidin, a novel histone deacetylase inhibitor, inhibited the proliferation of tumor cells via induction of p21 WAF1/Cip1 . In this study, we determined the molecular mechanisms by which apicidin induced the p21 WAF1/Cip1 gene expression in HeLa cells. Apicidin induced p21 WAF1/Cip1 mRNA independent of the de novo protein synthesis and activated the p21 WAF1/Cip1 promoter through Sp1-3 site located at ؊82 and ؊77 relative to the transcription start site. This transcriptional activation appears to be mediated by protein kinase C (PKC), because calphostin C, a PKC inhibitor, significantly attenuated the activation of p21 WAF1/Cip1 promoter via Sp1 sites, which was accompanied by a marked suppression of p21 WAF1/Cip1 mRNA and protein expression induced by apicidin. Consistent with the transcriptional activation of p21 WAF1/Cip1 promoter by apicidin, apicidin treatment led to the translocation of PKC⑀ from cytosolic to particulate fraction, which was reversed by pretreatment with calphostin C, indicating the involvement of PKC in the transcriptional activation of p21 WAF1/Cip1 via Sp1 sites by apicidin. However, the PKC-mediated transcriptional activation of p21 WAF1/Cip1 by apicidin appears to be independent of the histone hyperacetylation, because apicidin-induced histone hyperacetylation was not affected by calphostin C. Furthermore, a PKC activator, phorbol 12,13-dibutyrate, alone induced the transcriptional activation of p21 WAF1/Cip1 promoter, p21 WAF1/Cip1 mRNA, and protein expression without induction of the histone hyperacetylation, suggesting that the transcriptional activation of p21 WAF1/Cip1 by apicidin might have been mediated by a mechanism other than chromatin remodeling through the histone hyperacetylation. Taken together, these results suggest that the PKC signaling pathway plays a pivotal role in the transcriptional activation of the p21 WAF1/Cip1 gene by apicidin.