ATAD2 Is a Novel Cofactor for MYC, Overexpressed and Amplified in Aggressive Tumors

Abstract

The E2F and MYC transcription factors are critical regulators of cell proliferation and contribute to the development of human cancers. Here, we report on the identification of a novel E2F target gene, ATAD2, the predicted protein product of which contains both a bromodomain and an ATPase domain. The pRB-E2F pathway regulates ATAD2 expression, which is limiting for the entry into the S phase of the cell cycle. We show that ATAD2 binds the MYC oncogene and stimulates its transcriptional activity. ATAD2 maps to chromosome 8q24, 4.3 Mb distal to MYC, in a region that is frequently found amplified in cancer. Consistent with this, we show that ATAD2 expression is high in several human tumors and that the expression levels correlate with clinical outcome of breast cancer patients. We suggest that ATAD2 links the E2F and MYC pathways and contributes to the development of aggressive cancer through the enhancement of MYC-dependent transcription. [Cancer Res 2009;69(21):8491-8]

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

“…Interestingly, Atad2-L was strictly associated with the nuclear non-soluble fraction, suggesting its tight association with chromatin and/or nuclear matrix ( Figure 3a, lanes 2 and 4). This is in agreement with the data of (Ciro et al, 2009), who observed the association of human ATAD2, which corresponds to Adat2-L, with the nuclear matrix. In contrast, the short form was essentially present in the soluble fraction ( Figure 3a, lane 3).…”

“…Here, we identified ATAD2 as one of these genes and showed its overexpression, compared with normal somatic tissues, in a strikingly large number of unrelated somatic cancers. These data confirm and extend the observation of Ciro et al (2009), who had detected a frequent overexpression of ATAD2 in seven different cancer types. In addition, detailed clinical information on a cohort of lung and breast cancer patients allowed us to evidence Figure 6 The ATAD2 knock-down induces global transcription changes associated with increased histone dynamics.…”

“…This correlation was not, however, confirmed in the case of lymphoma, suggesting that ATAD2 may cooperate with cell type-specific factors to induce an aggressive behavior of the cells, a hypothesis which is in agreement with its demonstrated involvement in the estrogen and androgen receptor pathways and its activity as an MYC co-factor (Zou et al, 2007(Zou et al, , 2009Ciro et al, 2009).…”

“…Another study reveals its action as an androgen-receptor coactivator, overexpressed in hormone-independent prostate cancer cell lines as well as in a subset of prostate cancers (Zou et al, 2009). All these investigations also highlighted the activity of ATAD2 as a transcriptional regulator, which, in addition to the estrogen and androgen receptors pathways, functions as a MYC cofactor (Ciro et al, 2009). Although the aberrant expression of male germ cell genes in cancer cells has already been demonstrated, their contribution to cell transformation remains poorly understood.…”

“…In addition, a genetic screen in Caenorabditis elegans suggests its involvement in the silencing of repeated transgenes (Tseng et al, 2007). Interestingly, recently several laboratories have reported the overexpression of human ATAD2 in different cancer types, and have attempted to understand its potential contribution to oncogenesis (Zou et al, 2007(Zou et al, , 2009Ciro et al, 2009). One of these studies shows that human ATAD2 is a target of estrogen in human breast cancer cells, and controls the estrogen-dependent expression of several ER-a target genes (Zou et al, 2007).…”