Heat Shock Protein 90 Promotes RNA Helicase DDX5 Accumulation and Exacerbates Liver Cancer by Inhibiting Autophagy

Abstract

Background & Aims: Hepatocellular carcinoma (HCC), the main type of liver cancer, has a high morbidity and mortality rate and poor prognosis. RNA helicase DDX5, which acts as a transcriptional co-regulator, is overexpressed in most malignant tumors and promotes cancer cell activities. Heat shock protein 90 (HSP90) is an important molecular chaperone in the conformational maturation and stabilization of numerous proteins involved in cell growth or survival.

Methods: DDX5 mRNA and protein expression in surgically resected HCC tissues from 24 Asian patients were detected by quantitative real-time PCR and western blotting, respectively. The interaction of DDX5-HSP90 was testified by molecular docking, immunoprecipitation and laser scanning confocal microscopy (LSCM). The signal of autophagy was detected by western blotting. The cells functions and signalling pathway of DDX5 was examined in two HCC cell lines. Two different murine HCC xenograft models were used to determine the function of DDX5 and the therapeutic effect of HSP90 inhibitor.

Results: High levels of DDX5 protein were associated with poor prognosis.  HSP90 interacted directly with DDX5 and protected DDX5 protein from AMPK/ULK1-regulated autophagy degradation. The subsequent accumulation of DDX5 protein promoted the malignant phenotype of HCC by activating the β-catenin signaling pathway.  Silence of DDX5 or treatment with HSP90 inhibitor both blocks in vivo tumor growth in murine HCC xenograft model.

Conclusions: HSP90 interacts with DDX5 protein and subsequently protects DDX5 protein from AMPK/ULK1-regulated autophagic degradation. DDX5 or HSP90 is the potential therapeutic target for HCC.

Funding Statement: National Natural Science Foundation of China (81672467, 81702773, 81702389), Major National R&D Project (2018ZX10723204, 2018ZX10302205) and Natural Science Foundation of Beijing (7172207).

Declaration of Interests: The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.

Ethics Approval Statement: This study was approved by the Ethics Committee at each hospital and all patients provided informed consent prior to participation in the study.