p38α/S1P/SREBP2 activation by the SAM-competitive EZH2 inhibitor GSK343 limits its anticancer activity but creates a druggable vulnerability in hepatocellular carcinoma.

Enhancer of zeste homolog 2 (EZH2) mediates epigenetic gene silencing via tri-methylation of histone H3 lysine 27 (H3K27-me3). Increased expression of EZH2 is frequently detected in various cancers including hepatocellular carcinoma (HCC), which is associated with the silencing of tumor suppressor genes. S-adenosyl--methionine (SAM)-competitive EZH2 inhibitors fall into the major category of EZH2 inhibitors for cancer therapy.

and identification of inhibitory activities of sorafenib on histone deacetylases in hepatocellular carcinoma cells.

Although sorafenib has been approved for treating hepatocellular carcinoma (HCC), clinical results are not satisfactory. Polypharmacology (one drug with multiple molecular targets) is viewed as an attractive strategy for identifying novel mechanisms of a drug and then rationally designing more-effective next-generation therapeutic agents. In this study, a polypharmacological study of sorafenib was performed by mining the next-generation Connectivity Map (CMap) database, CLUE (https://clue.

In silico and experimental analyses predict the therapeutic value of an EZH2 inhibitor GSK343 against hepatocellular carcinoma through the induction of metallothionein genes.

There are currently no effective molecular targeted therapies for hepatocellular carcinoma (HCC), the third leading cause of cancer-related death worldwide. Enhancer of zeste homolog 2 (EZH2), a histone H3 lysine 27 (H3K27)-specific methyltransferase, has been emerged as novel anticancer target. Our previous study has demonstrated that GSK343, an S-adenosyl-L-methionine (SAM)-competitive inhibitor of EZH2, induces autophagy and enhances drug sensitivity in cancer cells including HCC.

Angiotensin II downregulates ACE2-mediated enhancement of MMP-2 activity in human cardiofibroblasts.

Angiotensin converting enzyme II (ACE2) is a component of the renin-angiotensin system (RAS) that negatively regulates angiotensin II (Ang II). Ang II, in turn, affects the expression of matrix metalloproteinases (MMPs) to induce heart remodeling. The specific mechanisms by which ACE2 regulates MMP-2, however, remain unclear.

Circulating matrix metalloproteinase-2 and -9 enzyme activities in the children with ventricular septal defect.

Ventricular septal defect (VSD) is the most common form of congenital heart diseases. Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases involved in causal cardiac tissue remodeling. We studied the changes of circulating MMP-2 and MMP-9 activities in the patients with VSD severity and closure.