Abstract
USP22, a member of the deubiquitinases (DUBs) family, is known to be a key subunit of the human Spt-Ada-Gcn5 acetyltransferase (hSAGA) transcriptional cofactor complex. Within hSAGA, USP22 removes ubiquitin from histone proteins, thus regulating the transcription and expression of downstream genes. USP22 plays important roles in many cancers; however, its effect and the mechanism underlying HCC chemoresistance remain unclear. In the present study, we found that USP22 was highly expressed in chemoresistant HCC tissues and cells and was correlated with the prognosis of HCC patients who received chemotherapy. Silencing USP22 in chemoresistant HCC Bel/Fu cells dramatically inhibited proliferation, migration, invasion and epithelial-mesenchymal transition in vitro; suppressed tumorigenic and metastatic capacities in vivo; and inhibited drug resistance-related proteins (MDR1, LRP, MRP1). Mechanistically, we found that USP22 knockdown exerts its function through down-regulating PI3K and activating Smad4, which inhibited phosphorylation of Akt. Silencing Smad4 blocked USP22 knockdown-induced Akt inhibition in Bel/Fu cells. Our results, for the first time, provide evidence that USP22 plays a critical role in the development of chemoresistant HCC cells and that high USP22 expression serves as a molecular marker for the prognosis of HCC patients who undergo chemotherapy.
Highlights
Hepatocellular carcinoma (HCC) is one of the most common malignancies and accounts for the second highest cancer-related mortality
We found that Ubiquitin-specific protease 22 (USP22) was overexpressed in chemoresistant HCC tissues, indicating that USP22 might be correlated with the development of chemoresistance in HCC
To investigate whether USP22 is involved in HCC chemoresistance, the clinical data and tissues of 52 HCC patients who received TACE treatment after curative resection between 2009 and 2012 at the Second Hospital of Dalian Medical University were collected
Summary
Hepatocellular carcinoma (HCC) is one of the most common malignancies and accounts for the second highest cancer-related mortality. There are approximately 800,000 new cases of liver cancer and 750,000 deaths worldwide per year. There is a high incidence of HCC in China, with China alone accounting for approximately 50% of the total number of cases and deaths [1, 2]. USP22 consists of 525 amino acids, and there is a putative ubiquitin hydrolase containing a C-terminal peptidase domain and an N-terminal UBP-type zinc finger motif that mediates www.impactjournals.com/oncotarget the association of these enzymes with other proteins [5,6,7]. As a crucial subtype of human Spt-Ada-Gcn acetyltransferase (hSAGA), USP22 promotes the stability of multiple cancer-associated protein targets through deubiquitylation and influences oncogene accumulation [7, 8]. USP22 has been considered to be a protooncogene because its expression is significantly upregulated in malignant tumors of several tissues, including the cervix, colon and liver [9, 10], and it participates in regulating proliferation, metastasis and recurrence [6]
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