Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide with lack of effective systemic chemotherapy. In this study, we aimed to evaluate the value of ATPase family AAA domain-containing protein 2 (ATAD2) as a biomarker and potential therapeutic target for HCC. The expression of ATAD2 was tested in different HCC patient cohorts by immunohistochemistry and comparative transcriptional analysis. The co-expression of ATAD2 and proliferation markers was compared during liver regeneration and malignancy with different bioinformatics tools. The cellular effects of ATAD2 inactivation in liver malignancy was tested on cell cycle, apoptosis, and colony formation ability as well as tumor formation using RNA interference. The genes affected by ATAD2 inactivation in three different HCC cell lines were identified by global gene expression profiling and bioinformatics tools. ATAD2 overexpression is closely correlated with HCC tumor stage. There was gradual increase from dysplasia, well-differentiated and poorly-differentiated HCC, respectively. We also observed transient upregulation of ATAD2 expression during rat liver regeneration in parallel to changes in Ki-67 expression. ATAD2 knockdown resulted in apoptosis and decreased cell survival in vitro and decreased tumor formation in some HCC cell lines. However, three other HCC cell lines tested were not affected. Similarly, gene expression response to ATAD2 inactivation in different HCC cell lines was highly heterogeneous. ATAD2 is a potential proliferation marker for liver regeneration and HCC. It may also serve as a therapeutic target despite heterogeneous response of malignant cells.
Highlights
The AAA + ATPase and bromodomain factor ATAD2/ ANCCA (ATAD2) is composed of two AAA + domains and a bromodomain that recognizes acetylated histones [1]
To assess the clinical relevance of ATAD2 in Hepatocellular carcinoma (HCC), we surveyed its expression by immunohistochemistry in 7 normal liver tissues, 9 low-grade dysplastic nodules (LGDN), 18 high-grade dysplastic nodules (HGDN) and 27 HCC cases
We showed that freshly isolated human hepatocytes lack detectable ATAD2 protein in contrast to nine different HCC cell lines all expressing it
Summary
The AAA + ATPase and bromodomain factor ATAD2/ ANCCA (ATAD2) is composed of two AAA + domains and a bromodomain that recognizes acetylated histones [1]. ATAD2 has been referred to as a “generalist facilitator of chromatin dynamics” based on demonstrations where histone acetylation guides ATAD2 to chromatin, resulting in an overall increase of chromatin accessibility and histone dynamics [2]. ATAD2 bromodomain was shown to recognize di-acetylated histones, and it associates with H4K5acK12ac modifications found on newly synthesized histones following DNA replication, suggesting a critical role for ATAD2 following DNA replication [3]. Based on structural studies with its yeast homolog, ATAD2 was proposed to form a hexameric complex and to facilitate H3-H4 loading by binding to histone tails [4]. Shahnejat-Bushehri and Ehrenhofer-Murray [5] reported that the yeast homolog of ATAD2 is a deposition factor for CENP-A homolog with help from HJURP homolog, acting as a co-chaperon for centrosome assembly
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