USP14 maintains HIF1-\u03b1 stabilization via its deubiquitination activity in hepatocellular carcinoma

Chi Lv,Shan Wei,Shengli Wang,Kai Zeng,Ge Sun,Yue Zhao,Yefu Liu,Yiming Meng,Chunyu Wang,Lin Lin

doi:10.1038/s41419-021-04089-6

Abstract

Hepatocellular carcinoma (HCC) is the most common visceral neoplasms with its heterogeneity and high rate of recurrence. HCC is characterized to be delayed diagnosis and the development of resistant disease. However, the molecular mechanism for HCC pathogenesis and progression remains largely unknown. Here, we demonstrated that ubiquitin-specific protease14 (USP14) is highly expressed in HCC samples, and the higher expression of USP14 is positively correlated with poor prognosis. Interestingly, USP14 is involved in the maintenance of HIF1-α stability to activate HIF1-α-induced transactivation via its deubiquitinase activity. USP14 depletion or its specific inhibitor IU1 treatment decreased cell proliferation, invasion, migration, and Vascular Mimicry (VM) formation even under hypoxia conditions in HCC cell lines. Moreover, we provided the evidence to show that knockdown of USP14 or USP14 inhibitor (IU1) treatment inhibited tumor growth in tumor-bearing nude mice. Our findings suggest that USP14 maintains HIF1-α stability through its deubiquitination activity, providing a potential biomarker for the early diagnosis and therapy of HCC.

Highlights

Hepatocellular carcinoma (HCC) is one of the most serious carcinomas, with a 5-year survival rate is 14–18%
ubiquitin-specific protease14 (USP14) is highly expressed in HCC samples, and the higher transcriptional activity of HIF1-α, we turned to analyze the expression of USP14 is positively correlated with poor mechanism underlying the modulation function of USP14 on prognosis
USP14 depletion significantly decreased HIF1-α results showed that USP14 mRNA expression was significantly protein level, but not HIF1-α mRNA level in HCC cells, suggesting higher in primary HCC tissues than that in normal liver tissues that USP14 may be involved in the maintenance of HIF1-α (Figure S1A)

Summary

INTRODUCTION

Hepatocellular carcinoma (HCC) is one of the most serious carcinomas, with a 5-year survival rate is 14–18%. It has been mentioned that some proteins involved in the maintenance of HIF1-α stability play crucial roles in tumorigenesis and progression of HCC. Ubiquitin-specific protease 22 (USP22) stabilizes HIF1-α to promote hypoxia-mediated HCC stemness and glycolysis by its deubiquitinase activity [9]. CDC20 as a cell cycle regulator mediates PHD3 degradation to increase the stability of HIF1-α in HCC [10]. Our results have shown that USP14 participates in the maintenance of HIF1-α stability and enhances HIF1-α-induced transcriptional activity via its deubiquitination activity in HCC cell. USP14 specific inhibitor IU1 significantly suppresses cell growth, demonstrated that HIF1-α-mediated transcriptional activity was migration, and VM formation in HCC. Taken stability and enhancement of HIF1-α activity, suggesting USP14 together, our results suggest that USP14 enhances HIF1-αwould be a potential diagnosis biomarker and therapeutic target mediated transactivation

RESULTS

Lv et al 3

MATERIALS AND METHODS

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