Abstract
Hyperactivation of the transcriptional factor E2F1 occurs frequently in human cancers and contributes to malignant progression. E2F1 activity is regulated by proteolysis mediated by the ubiquitin–proteasome system. However, the deubiquitylase that controls E2F1 ubiquitylation and stability remains undefined. Here we demonstrate that the deubiquitylase POH1 stabilizes E2F1 protein through binding to and deubiquitylating E2F1. Conditional knockout of Poh1 alleles results in reduced E2F1 expression in primary mouse liver cells. The POH1-mediated regulation of E2F1 expression strengthens E2F1-downstream prosurvival signals, including upregulation of Survivin and FOXM1 protein levels, and efficiently facilitates tumour growth of liver cancer cells in nude mice. Importantly, human hepatocellular carcinomas (HCCs) recapitulate POH1 regulation of E2F1 expression, as nuclear abundance of POH1 is increased in HCCs and correlates with E2F1 overexpression and tumour growth. Thus, our study suggests that the hyperactivated POH1–E2F1 regulation may contribute to the development of liver cancer.
Highlights
Hyperactivation of the transcriptional factor E2F transcription factor 1 (E2F1) occurs frequently in human cancers and contributes to malignant progression
To identify deubiquitinating enzymes (DUBs) with the capacity of regulating E2F1 expression, we initially screened 37 DUBs, expression of which are relatively high in human liver tissues based on in sillico EST profile analysis
Our present study provides evidence that POH1 deubiquitinates and stabilizes the master transcription factor E2F1 and functions as a tumour-promoting protein in hepatocellular carcinomas (HCCs)
Summary
Hyperactivation of the transcriptional factor E2F1 occurs frequently in human cancers and contributes to malignant progression. The POH1-mediated regulation of E2F1 expression strengthens E2F1-downstream prosurvival signals, including upregulation of Survivin and FOXM1 protein levels, and efficiently facilitates tumour growth of liver cancer cells in nude mice. Our study suggests that the hyperactivated POH1–E2F1 regulation may contribute to the development of liver cancer. POH1 functions in various biological processes, including double-strand DNA break responses[30], embryonic stem cell differentiation[31], aggresome disassembly and clearance[32], cellular viability[33,34], multidrug resistance[35] and protein stability[36,37,38]. We identify POH1 as the deubiquitinating enzyme that stabilizes E2F1 and demonstrate that aberrant hyperactivity of POH1–E2F1 regulation promotes liver tumour formation. Our study describes a previously unknown mechanism by which E2F1 expression is regulated as well as its implication in tumorigenesis
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