CBX6 is negatively regulated by EZH2 and plays a potential tumor suppressor role in breast cancer.

Chromobox 6 (CBX6) is a subunit of Polycomb Repressive Complex 1 (PRC1) that mediates epigenetic gene repression and acts as an oncogene or tumor suppressor in a cancer type-dependent manner. The specific function of CBX6 in breast cancer is currently undefined. In this study, a comprehensive analysis of The Cancer Genome Atlas (TCGA) dataset led to the identification of CBX6 as a consistently downregulated gene in breast cancer. We provided evidence showing enhancer of zeste homolog 2 (EZH2) negatively regulated CBX6 expression in a Polycomb Repressive Complex 2 (PRC2)-dependent manner. Exogenous overexpression of CBX6 inhibited cell proliferation and colony formation, and induced cell cycle arrest along with suppression of migration and invasion of breast cancer cells in vitro. Microarray analyses revealed that CBX6 governs a complex gene expression program. Moreover, CBX6 induced significant downregulation of bone marrow stromal cell antigen-2 (BST2), a potential therapeutic target, via interactions with its promoter region. Our collective findings support a tumor suppressor role of CBX6 in breast cancer.

Histone H3.3K27M Mobilizes Multiple Cancer/Testis (CT) Antigens in Pediatric Glioma.

Lysine to methionine mutations at position 27 (K27M) in the histone H3 (H3.3 and H3.1) are highly prevalent in pediatric high-grade gliomas (HGG) that arise in the midline of the central nervous system. H3K27M perturbs the activity of polycomb repressor complex 2 and correlates with DNA hypomethylation; however, the pathways whereby H3K27M drives the development of pediatric HGG remain poorly understood. To understand the mechanism of pediatric HGG development driven by H3.3K27M and discover potential therapeutic targets or biomarkers, we established pediatric glioma cell model systems harboring H3.3K27M and performed microarray analysis. H3.3K27M caused the upregulation of multiple cancer/testis (CT) antigens, such as ADAMTS1, ADAM23, SPANXA1, SPANXB1/2, IL13RA2, VCY, and VCX3A, in pediatric glioma cells. Chromatin immunoprecipitation analysis from H3.3K27M cells revealed decreased H3K27me3 levels and increased H3K4me3 levels on the VCX3A promoter. Knockdown of VCX3A by siRNA significantly inhibited the growth of pediatric glioma cells harboring H3.3K27M. Overexpression of VCX3A/B genes stimulated the expression of several HLA genes, including HLA-A, HLA-B, HLA-E, HLA-F, and HLA-G The expression of VCX3A in pediatric HGG was confirmed using a tissue microarray. Gene set enrichment analysis revealed that CT antigens are enriched in pediatric HGG clinical specimens with H3.3K27M, with the upregulation of IL13RA2 contributing to the enrichment significantly. These results indicate that the upregulation of CT antigens, such as VCX3A and IL13RA2, correlates with pediatric gliomagenesis. Mol Cancer Res; 16(4); 623-33. ©2018 AACR.

Production of bFGF monoclonal antibody and its inhibition of metastasis in Lewis lung carcinoma.

Basic fibroblast growth factor (bFGF) and fibroblast growth factor receptor 1 (FGFR1) are associated with drug resistance in lung cancer. In the present study, mouse monoclonal antibodies (mAb) against human bFGF, targeting the binding site of bFGF with FGFR1 were produced, and the antitumor activity and inhibition of metastasis was studied in Lewis lung carcinoma (LLC). A total of four hybridoma cell strains that stably secreted bFGF mAb were obtained. mAbE12 was selected as the most effective for use in the following studies, with a relative affinity constant of 5.66x108 l/mol. mAbE12 was demonstrated to inhibit cell proliferation and tumor growth in vitro and in vivo. Furthermore, mAbE12 blocked migration and metastasis of LLC cells in vitro and in vivo. This occurred due to a mAbE12­induced upregulation of E­cadherin expression through the protein kinase B­glycogen synthase kinase 3 ß­Snail pathway. These results suggested that mAbE12 may be a potential antibody for the treatment of lung cancer.

Chrysin-organogermanium (IV) complex induced Colo205 cell apoptosis-associated mitochondrial function and anti-angiogenesis.

Colorectal cancer, a kind of malignant cancer, has more than 1 million new patients and results in 0.5 million deaths every year globally based on the estimation of Globocan in 2008. One of the most important issues against colon cancer is tumor metastasis. Anti-angiogenesis, a form of targeted therapy uses drugs or other substances to prevent the new blood vessel formation, which is critical for tumor metastasis. In our previous studies, we have demonstrated a simple method to synthesize Chry-Ge complex through the reaction between chrysin and triphenylgermanium bromide. In this work, we investigated the mechanism of Chry-Ge induced Colo205 cell apoptosis. We found that Chry-Ge could induce apoptosis in Colo205 cells in mitochondrial-dependent pathway, cause the reorganization of cytoskeleton and induce the damage of nucleus in Colo205 cells. Besides, Chry-Ge was also found to induce membrane ultrastructural changes in Colo205 cells by AFM. Further, we found that Chry-Ge can inhibit tube formation of human umbilical vascular endothelial cell in vitro. Chry-Ge was also tested in vivo in the chicken chorioallantoic membrane (CAM) assay and found to inhibit bFGF-treated CAMs development. These results suggested that Chry-Ge could induce Colo205 cell apoptosis by mitochondrial pathway and anti-angiogenesis, highlighting the use of organic germanium agents for the treatment of colorectal cancer.