PSMD4 Sensitizes Hepatoma Cells To ER-stress Induced Apoptosis

Hepatocellular carcinoma(HCC)is one of several cancers in which a continued increase of morbidity has been observed in the past few years.Moreover,the prognosis of HCC patients were rather poor owing to frequent recurrence after ablation or resection.Sorafenib is the first targeted agent for advanced HCC with only limited effect.Therefore,it is rather urgent to identify novel molecular targets for pharmalogical intervention and predictors for HCC patient outcome.The endoplasmic-reticulum(ER)stress response is a cellular process which is triggered under various conditions.ER stress disturbs the folding of proteins in ER.Eukaryotic cells have developed an evolutionarily conserved process,the unfolded protein response(UPR)to clear unfolded proteins and restore ER homeostasis.When ER stress cannot be alleviated,normal cellular activities will be destroyed,eventually leading to cell death.Accumulating evidence implicates that ER stress-induced cellular dysfunction and cell death contribute to many diseases,making modulators of ER stress pathways potential targets for intervention.Protein substrates are targeted for proteolysis by the ubiquitin pathway through the addition of a polyubiquitin chain before being degraded by the 26 S proteasome.Previously,a subunit of the proteasome,PSMD4,was identified by our lab.PSMD4 was able to bind to polyubiquitin in vitro as a substrate recognition component.The ubiquitin-binding PSMD4 protein serves as an ubiquitin receptor and delivers substrates to 26 s proteasome for degradation.However,the role of PSMD4 in ER stress-induced HCC cell apoptosis has not been extensively investigated.Thus,by virtue of clinical specimens,HCC cell lines and ER stress models,we investigated the clinical significance of PSMD4 in predicting HCC patient outcome,and evaluated the effect of PSMD4 on ER stress-induced HCC cell apoptosis,as well as the underlying mechanism.Our results revealed that PSMD4 levels in HCC correlates with patient outcome,and PSMD4 can promote ER stress-induced apoptosis of HCC cells through preventing the degradation of ATF4.In conclusion,PSMD4 is an valuable predictor for patient prognosis,and also a novel regulator of ER stress-induced HCC cell apoptosis.