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The role of the cancer/testis antigen CAGE in drug resistance was investigated. The drug-resistant human melanoma Malme3M (Malme3M R ) and the human hepatic cancer cell line SNU387 (SNU387 R ) showed in vivo drug resistance and CAGE induction. Induction of CAGE resulted from decreased expression and thereby displacement of DNA methyltransferase 1(DNMT1) from CAGE promoter sequences. Various drugs induce expression of CAGE by decreasing expression of DNMT1, and hypomethylation of CAGE was correlated with the increased expression of CAGE. Down-regulation of CAGE in these cell lines decreased invasion and enhanced drug sensitivity resulting from increased apoptosis. Down-regulation of CAGE also led to decreased anchorage-independent growth. Down-regulation of CAGE led to increased expression of p53, suggesting that CAGE may act as a negative regulator of p53. Down-regulation of p53 enhanced resistance to drugs and prevented drugs from exerting apoptotic effects. In SNU387 R cells, CAGE induced the interaction between histone deacetylase 2 (HDAC2) and Snail, which exerted a negative effect on p53 expression. Chromatin immunoprecipitation assay showed that CAGE, through interaction with HDAC2, exerted a negative effect on p53 expression in Malme3M R cells. These results suggest that CAGE confers drug resistance by regulating expression of p53 through HDAC2. Taken together, these results show the potential value of CAGE as a target for the development of cancer therapeutics.

We have developed multifunctional fluorescent surface enhanced Raman spectroscopic tagging material (F-SERS dots) composed of silver nanoparticle-embedded silica spheres with fluorescent organic dye and specific Raman labels for multiplex targeting, tracking, and imaging of cellular/molecular events in the living organism. In this study, F-SERS dots fabricated with specific target antibodies (BAX and BAD) were employed for the detection of apoptosis. The F-SERS dots did not show any particular toxicity in several cell lines. The F-SERS dots could monitor the apoptosis effectively and simultaneously through fluorescent images as well as Raman signals in both cells and tissues with high selectivity. Our results clearly demonstrate that F-SERS dots can be easily applicable to multiplex analysis of diverse cellular/molecular events important for maintaining cellular homeostasis.

A new type of encoded bead, which uses surface-enhanced Raman scattering (SERS), is described for multiplex immunoassays. Silver nanoparticles were embedded in sulfonated polystyrene (PS) beads via a polyol method, and they were used as SERS-active substrates. Raman-label organic compounds such as 4-methylbenzenethiol (4-MT), 2-naphthalenethiol (2-NT), and benzenethiol (BT) were then adsorbed onto the silver nanoparticles in the sulfonated PS bead. Although only three kinds of encoding have been demonstrated here, various combinations of these Raman-label organic compounds have the potential to give a large number of tags. The Raman-label-incorporated particles were then coated with a silica shell using tetraethoxyorthosilicate (TEOS) for chemical stability and biocompatibility. The resulting beads showed unique and intense Raman signals for the labeled organic compounds. We demonstrated that SERS-encoded beads could be used for multiplex detection with a model using streptavidin and p53. In our system, the binding event of target molecules and the type of ligand can be simultaneously recognized by Raman spectroscopy using a single laser-line excitation (514.5 nm).

Background:The role of HDAC3 in anti-cancer drug resistance remains unknown. Results: HDAC3 forms a negative feedback loop with miR-326 and regulates the response to anti-cancer drugs. Conclusion: HDAC3 forms a feedback loop with multiple miRNAs to regulate the response to anti-cancer drugs. Significance: miR-326 and HDAC3 serve as targets for the development of anti-cancer therapeutics.

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Histone deacetylase-3 (HDAC3) is involved in cellular proliferation, apoptosis and transcriptional repression. However, the role of HDAC3 in angiogenesis remains unknown. HDAC3 negatively regulated the expression of angiogenic factors, such as VEGF and plasminogen activator inhibitor-1 (PAI-1). HDAC3 showed binding to promoter sequences of PAI-1. HDAC3 activity was necessary for the expression regulation of PAI-1 by HDAC3. VEGF decreased the expression of HDAC3, and the down-regulation of HDAC3 enhanced endothelial cell tube formation. HDAC3 negatively regulated tumor-induced angiogenic potential. We show the novel role of HDAC3 as a negative regulator of angiogenesis. [BMB Reports 2014; 47(4): 227-232]