Enhancer of zeste homolog 2 (EZH2) is an important member of the epigenetic regulatory factor
polycomb group proteins (PcG) and is abnormally expressed in a wide variety of
tumors, including
osteosarcoma. Scientists consider EZH2 as an attractive target for the treatment of
osteosarcoma and have found many potential EZH inhibitors, such as GlaxoSmithKline 343 (
GSK343). It has been reported that
GSK343 can be used as an inhibitor in different types of
cancer. This study demonstrated that
GSK343 not only induced apoptosis by increasing cleaved Casp-3 and
poly ADP-ribose polymerase (PARP) expression, but also induced autophagic cell death by inhibiting p62 expression. Apoptosis and autophagic cell death induced by
GSK343 were confirmed by the high expression of cleaved
caspase-3, LC3-II and transmission electron microscopy.
GSK343 inhibited the expression of EZH2 and c-Myc. Additionally,
GSK343 inhibited the expression of FUSE
binding protein 1 (FBP1), which was identified by its regulatory effects on c-Myc expression. Since c-Myc is a common target of EZH2 and FBP1, and
GSK343 inhibited the expression of these proliferation-promoting
proteins, a mutual regulatory mechanism between EZH2 and FBP1 was proposed. The knockdown of EZH2 suppressed the expression of FBP1; similarly, the knockdown of FBP1 suppressed the expression of EZH2. These results suggest the mutual regulatory association between EZH2 and FBP1. The knockdown of either EZH2 or FBP1 accelerated the sensitivity of
osteosarcoma cells to
GSK343. Based on these results, this study clarified that
GSK343, an EZH2 inhibitor, may have potential for use in the treatment of
osteosarcoma. The underlying mechanisms of the effects of
GSK343 are partly mediated by its inhibitory activity against c-Myc and its regulators (EZH2 and FBP1).