Abstract
Apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1) is a dual function protein; in addition to its DNA repair activity, it can stimulate DNA binding activity of numerous transcription factors as a reduction-oxidation (redox) factor. APE1/Ref-1 has been found to be a potent activator of wild-type p53 (wtp53) DNA binding in vitro and in vivo. Although p53 is mutated in most types of human cancer including hepatocellular carcinoma (HCC), little is known about whether APE1/Ref-1 can regulate mutant p53 (mutp53). Herein, we reported the increased APE1/Ref-1 protein and accumulation of mutp53 in HCC by immunohistochemistry. Of note, it was observed that APE1/Ref-1 high-expression and mutp53 expression were associated with carcinogenesis and progression of HCC. To determine whether APE1/Ref-1 regulates DNA binding of mutp53, we performed electromobility shift assays (EMSAs) and quantitative chromatin immunoprecipitation (ChIP) assays in HCC cell lines. In contrast to sequence-specific and DNA structure-dependent binding of wtp53, reduced mutp53 efficiently bound to nonlinear DNA, but not to linear DNA. Notably, overexpression of APE1/Ref-1 resulted in increased DNA binding activity of mutp53, while downregulation of APE1/Ref-1 caused a marked decrease of mutp53 DNA binding. In addition, APE1/Ref-1 could not potentiate the accumulation of p21 mRNA and protein in mutp53 cells. These data indicate that APE1/Ref-1 can stimulate mutp53 DNA binding in a redox-dependent manner.
Highlights
Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancer-related mortality worldwide
We investigated the expression of APE1 in 10 normal liver tissues, 40 liver cirrhosis tissues and 103 cases of HCC tissues using immunohistochemistry
Our data indicated that the increased APE1 level, cytoplasmic localization of APE1 and mutp53 expression were relevant to neoplastic alteration and poor differentiation of HCC
Summary
Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancer-related mortality worldwide. It has a five year natural mortality rate of >95%, Key words: APE1/Ref-1, p53 DNA binding, mutant p53 and it affects >500,000 people in the world each year; >50% of the new HCC cases and deaths have occurred in China [1]. Several studies demonstrated that APE1 was high-expressed in several human tumors including prostate, osteosarcomas, lung and cervical carcinoma, and the elevated APE1 level was associated with chemo- and radioresistance and poor clinical outcome [4,5]. Tumor cells often show increased expression level and altered subcellular localization of APE1, and are associated with chemo- and radioresistance and tumor carcinogenesis and progression
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