PSMD4 drives progression of hepatocellular carcinoma via Akt/COX2 pathway and p53 inhibition.

The ubiquitin-dependent proteolytic pathway is crucial for cellular regulation, including control of the cell cycle, differentiation, and apoptosis. Proteasome 26S Subunit Ubiquitin Receptor, Non-ATPase 4, (PSMD4) is a member of the ubiquitin proteasome family that is upregulated in multiple solid tumors, including hepatocellular carcinoma (HCC), and the existence of PSMD4 is associated with unfavorable prognosis. In this study, transcriptome sequencing of HCC tissues and non-tumor hepatic tissues from the public database Cancer Genome Atlas (TGCA) revealed a high expression of PSMD4. Additionally, PSMD4 loss in HCC cells suppressed the tumor development in mouse xenograft model. PSMD4, which is maintained by inflammatory factors secreted from tumor matrix cells, positively mediates cell growth and is associated with Akt/GSK-3β/ cyclooxygenase2 (COX2) pathway activation, inhibition of p53 promoter activity, and increased p53 degradation. However, the domain without the C-terminus (VWA+UIM1/2) sustained the activation of p53 transcription. Thus, our findings suggest that PSMD4 is involved in HCC tumor growth through COX2 expression and p53 downregulation. Therapeutic strategies targeting PSMD4 and its downstream effectors could be used for the treatment of PSMD4-abundant HCC patients.