This month’s featured article is from a research group led by Pei-Ming Yang at Mackay Memorial Hospital in Taipei, Taiwan. The article was published on 29 January 2016 in the journal Oncoscience.
This study investigates the potential of GSK343, an inhibitor to EZH2, as a molecular therapeutic for hepatocellular carcinoma (HCC), which is the third leading cause of cancer-related death in the world. EZH2, a histone H3 lysine 27-specific methyltransferase, is frequently overexpressed in tumors, and thus has been targeted for anticancer treatment by many investigators.
In the current study, the authors mined cancer genome data sets to find that EZH2 is commonly up-regulated during HCC, both at the transcript and protein levels. Next, the authors treated HepG2 cells (a HCC cell line) with the EZH2 small molecule inhibitor GSK343, and found it to be potently cytotoxic to HepG2 cells. They also measured gene expression changes following GSK343 treatment using Phalanx Biotech’s Human OneArray Whole Genome Microarray.
Interestingly, they found that many metallothionein genes were among the most up-regulated genes following GSK343 treatment, and their positive expression was further validated using real-time PCR. The authors further showed that GSK343-mediated metallothionein induction was zinc-dependent, and required for the anticancer activity of GSK343. The authors further mined cancer genome databases to show that metallothionein expression is negatively correlated with EZH2 expression. A trend emerged showing up-regulation of EZH2 in cancer data sets, along with a down-regulation of metallothionein transcripts.
Overall, these studies show great potential of GSK343 as a small molecule inhibitor for the treatment of HCC. Future in vivo studies will be focused on showing that GSK343 can abolish EZH2 up-regulation and metallothionein down-regulation during HCC.
Liu TP et al. In silico and experimental analyses predict the therapeutic value of an EZH2 inhibitor GSK343 against hepatocellular carcinoma through the induction of metallothionein genes (2016). Oncoscience 3(1): 9-20.