Hepatocellular carcinoma is a leading cause of cancer-related death worldwide and the underlying pathophysiology of HCC is highly complex. In this study, we report that, in a bioinformatic screen of 2783 genes encoding metabolic enzymes, GNPAT, which encodes the enzyme glyceronephosphate O-acyltransferase, is amplified, upregulated, and highly correlated with poor clinical outcome in human HCC patients. High GNPAT expression in HCC was due to its amplification and transcriptional activation by the c-Myc/KDM1A complex. GNPAT compensated the oncogenic phenotypes in c-Myc-depleted HCC cells. Mechanistically, GNPAT recruited the enzyme USP30, which deubiquitylated and stabilized dynamin-related protein 1 (DRP1), thereby facilitating regulation of mitochondrial morphology, lipid metabolism, and hepatocarcinogenesis. Inhibition of GNPAT and DRP1 dramatically attenuated lipid metabolism and hepatocarcinogenesis. Furthermore, DRP1 mediated the oncogenic phenotypes driven by GNPAT. Taken tog...

Hepatocellular carcinoma (HCC) is one of the most common fatal cancers in the world. However, the underlying molecular mechanisms contributing to hepatocarcinogenesis are still unclear. A putative tumor suppressor gene, namely DLC-1 (frequently deleted in liver cancer) was identified and mapped at chromosome 8p21.3-22, a recurrently deleted region in human cancers. The gene exerts inhibitory effects on the cell proliferation of HCC cells. In this study, we investigated the biological function, and genetic and epigenetic status of this gene in human HCC. With in vitro GTPase activating proteins activity assay, we established that DLC-1 protein was a GTPase-activating protein specific for RhoA and Cdc42. Deletion of the DLC-1 gene was frequent in human HCC, as revealed by loss of heterozygosity analysis performed on 100 human HCC cases with markers mapped at the DLC-1 locus, and allelic losses ranging from 44% to 50% of the informative cases. However, somatic mutations of the DLC-1 ge...

The gene deleted in liver cancer-1 (DLC-1) is located on human chromosome 8p21-22, a region thought to harbor tumor suppressor genes on the basis of its frequent deletion or loss of heterozygosity in a variety of human cancers, including hepatocellular carcinoma (HCC). Deletion or altered expression of DLC-1 is common in HCC. In the current study, the subcellular localization of Dlc-1 protein was determined by immunostaining with antibody to DLC-1 and the possible tumor growth suppressor activity of DLC-1 was investigated by examining the effects of of DLC-1 cDNA transfection in two human HCC cell lines lacking expression of the endogenous gene. The results show that Dlc-1protein is localized in the cell cytoplasm, and the restoration of DLC-1 expression in HCC cells resulted in caspase-3-mediated apoptosis, inhibition of cell growth and invasiveness in vitro as well as in reduction of the ability of the cells to form tumors in athymic nude mice. These observations thus support the ...

Although histone deacetylase (HDAC) inhibitors are appreciated as a promising class of anticancer drugs, recent reports show that P-glycoprotein (P-gp) is induced by HDAC inhibitor treatment in cancer cells, resulting in multidrug resistance of cancer cells to other chemotherapeutic agents. In this study, we investigated the molecular mechanism of HDAC inhibitor induction of P-gp expression. HDAC inhibitor treatment causes cell type–specific induction of P-gp expression without changes in the CpG methylation status of the promoter region. In addition, our data show that HDAC inhibitor does not alter the DNA binding activity of Sp1 but facilitates both the recruitment of a coactivator complex that includes CAAT/enhancer binding protein β and pCAF and the dissociation of the repressive complex, HDAC1, to the Sp1 binding region. Subsequently, the hyperacetylated histone H3 becomes enriched in the promoter region, leading to RNA polymerase II recruitment to activate P-gp gene transcript...

El origen de la vida en nuestro universo sigue siendo en parte un misterio. Los humanos sabemos que la vida es una enfermedad letal, transmisible sexualmente. Las creencias reveladas, a través de doctrinas concebidas hace siglos, dan diversas exégesis sobre el orden del caos y sobre nuestro destino biológico.