Functional characterization of ATAD2 as a new cancer/testis factor and a predictor of poor prognosis in breast and lung cancers

Abstract

Cancer cells frequently express genes normally active in male germ cells. ATAD2 is one of them encoding a conserved factor harbouring an AAA type ATPase domain and a bromodomain. We show here that ATAD2 is highly expressed in testis as well as in many cancers of different origins and that its high expression is a strong predictor of rapid mortality in lung and breast cancers. These observations suggest that ATAD2 acts on upstream and basic cellular processes to enhance oncogenesis in a variety of unrelated cell types. Accordingly, our functional studies show that ATAD2 controls chromatin dynamics, genome transcriptional activities and apoptotic cell response. We could also highlight some of the important intrinsic properties of its two regulatory domains, including a functional cross-talk between the AAA ATPase domain and the bromodomain. Altogether, these data indicate that ATAD2 overexpression in somatic cells, by acting on basic properties of chromatin, may contribute to malignant transformation.

The bromodomain interaction module

“…BRDs of this family have not been extensively studied for binding to acetylated proteins although their involvement in disease has been described and their target sites will contribute to better understanding of their function [34]. The BRD of ATAD2 has been shown to immunoprecipitate histone H3 (K14 ac [68]) but this interaction has not been quantified yet, while the closely homologous KIAA1240 binds to histone H4 (K5 ac [33,69] [70]). Subfamily V of the human BRDs contains the transcriptional repressor tripartite motif-containing 66 (TRIM66) [71], the tripartite motif-containing 33 (TRIM33) [72], the transcriptional regulator transcriptional intermediary factor 1 (TIF1a) [73], the transcriptional regulators nuclear auto-antigen Sp-100 (SP100) [74], nuclear autoantigen Sp-110 (SP110) [75] and SP140 nuclear body protein (SP140) [76] as well as the SP140-like protein (LOC93349), the transcriptional repressor bromodomain adjacent to zinc finger domain 2A (BAZ2A) [77] and the bromodomain adjacent to zinc finger domain 2B (BAZ2B) [78].…”

ATAD2 is Highly Expressed in Ovarian Carcinomas and Indicates Poor Prognosis

“…High levels of ATAD2 correlate with poor survival and disease recurrence in patients with prostate and breast cancers, while RNAi-mediated knockdown of ATAD2 strongly inhibited hormone-dependent cancer cell proliferation (Hsia et al, 2009;Kalashnikova et al, 2010;. ATAD2 has been reported to be overexpressed, as an important risk factor, in several cancers such as prostate, breast and lung cancer (Ciró et al, 2009;Caron et al, 2010;Hsia et al, 2010). Recently, a few of studies have linked ATAD2 gene to ovarian cancer (Wrzeszczynski et al, 2011;Raeder et al, 2013).…”

Combined proteomic andin silicoapproaches to decipher post-meiotic male genome reprogramming in mice

“…This search enabled us to identify several bromodomaincontaining factors highly or specifically expressed in testis, including a double bromodomain-containing protein of the BET family, named Brdt [Govin et al 2006b;Moriniere et al 2009;Pivot-Pajot et al 2003;Shang et al 2004], and a factor with an AAA ATPase domain and a bromodomain, named Atad2 [Caron et al 2010]. In addition we found other chromatin related factors, such as Cdyl, a testisexpressed chromatin related factor, which contains a N-terminal chromodomain fused to a domain showing a high homology to the coenzyme A (CoA) binding pocket of enoyl-CoA hydratase ].…”