Geranylgeranylacetone promotes human osteosarcoma cell apoptosis by inducing the degradation of PRMT1 through the E3 ubiquitin ligase CHIP

Abstract

Geranylgeranylacetone (GGA), an inducer of heat shock proteins, exerts anticancer activity in some tumours. However, the effect of GGA on human osteosarcoma (OS) has not been reported. This work is designed to evaluate the effect of GGA on the proliferation and apoptosis of human OS cells and to explore the underlying mechanisms. It was found that GGA markedly inhibited the proliferation and induced apoptosis of U-2 OS cells in a dose-dependent manner and also up-regulated the expression of heat shock protein 70 (Hsp70). The degradation and ubiquitination of protein arginine N-methyltransferase 1 (PRMT1) were obviously enhanced in U-2 OS cells with CHIP overexpression and GGA treatment. The expression of PRMT1 was reversed in GGA-treated cell after CHIP knockdown. The turnover of PRMT1 was obviously faster in cells overexpressing CHIP than that in control cells. The methylation and activity of STAT3 were induced by PRMT1, resulting in the inhibition of FAS transcription. Overexpression of PRMT1 reversed the effect of GGA on activation of apoptosis-related proteins and U-2 OS cell apoptosis. The expressions of PRMT1 were significantly up-regulated in OS tissues compared with the adjacent normal tissues and benign bone tumours. In conclusion, GGA promotes the degradation of PRMT1 through the Hsp70-CHIP-mediated proteasome pathway, thereby inducing the FAS-triggered cell apoptosis. Inhibition of PRMT1 may be a potential therapeutic strategy for OS patients.

Keywords: Apoptosis; CHIP; Geranylgeranylacetone; PRMT1; ubiquitin.