EZH2/DUSP1/Akt signaling axis mediates the inhibitory effect of crebanine on hepatocellular carcinoma progression

Hepatocellular carcinoma (HCC) is characterized by a subtle onset, rapid development, and high malignancy. Traditional treatments have struggled to cure patients with advanced HCC. Crebanine is an isoquinoline aporphine alkaloid extracted from Stephania venosa. Few studies have focused on the therapeutic potential and molecular mechanisms of crebanine in HCC. Herein, to comprehensively evaluate the anti-HCC effect of crebanine in HCC and to further investigate the underlying mechanisms, potential therapeutic role of crebanine against HCC malignancy was assessed through in vitro and in vivo experiments. We carried out a panel of experiments covering cell viability, colony formation, apoptosis detection, migration, invasion and western blot analysis. Results revealed that crebanine suppresses proliferation, migration and invasion, and triggers apoptosis in HepG2 and Huh7 cells. Mechanistically, crebanine treatment increased DUSP1 expression while decreasing EZH2 and p-Akt expressions. Crebanine promoted DUSP1 transcription through repressing EZH2 expression, thereby inhibiting Akt phosphorylation. Knockdown of DUSP1 diminished the anti-HCC effects of crebanine while activating Akt signaling. Overexpression of EZH2 abolished crebanine-induced DUSP1 upregulation and the cytostatic effects in HCC both in vitro and vivo. Overall, crebanine effectively suppresses HCC tumor growth and progression via modulation of the EZH2/DUSP1/Akt signaling pathway. Crebanine shows potential as a promising therapeutic agent for HCC treatment.