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The Candidate Tumor Suppressor Gene ZAC Is Involved in Keratinocyte Differentiation and Its Expression Is Lost in Basal Cell Carcinomas

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The Candidate Tumor Suppressor Gene ZAC Is Involved in Keratinocyte Differentiation and Its Expression Is Lost in Basal Cell Carcinomas The Candidate Tumor Suppressor Gene ZAC Is Involved in Keratinocyte Differentiation and Its Expression Is Lost in Basal Cell Carcinomas Eugenia Basyuk,1,2 Vincent Coulon,3 Anne Le Digarcher,1 Marjorie Coisy-Quivy,2 Jean-Pierre Moles,3 Alberto Gandarillas,2,3 and Laurent Journot1 1Institut de Ge´nomique Fonctionnelle, CNRS-UMR5203, INSERM-U661, Universite´Montpellier 1, Universite´Montpellier 2; 2Institut de Ge´ne´tique Mole´culaire, CNRS-UMR5535, Universite´Montpellier 2; and 3Laboratoire de Dermatologie Mole´culaire, IURC, EA3754, Montpellier, France Abstract displays transactivation or transrepression activities depending ZAC is a zinc finger transcription factor that induces on the precise arrangement of its binding sites (2), and apoptosis and cell cycle arrest in various cell lines. accumulating evidence suggests its involvement in the control The corresponding gene is maternally imprinted and of cell proliferation and differentiation. Thus, inhibition of Zac1 localized on chromosome 6q24-q25, a region harboring expression by antisense oligonucleotides enhances pituitary cell an unidentified tumor suppressor gene for a variety proliferation (3), and expression of Lot1, the rat orthologue of of solid neoplasms. ZAC expression is lost or Zac1, is lost during the spontaneous transformation of rat ovary down-regulated in some breast, ovary, and pituitary surface epithelial cells in vitro (4). Interestingly, Zac1/Lot1 is tumors and in an in vitro model of ovary epithelial negatively regulated by epidermal growth factor, suggesting cell transformation. In the present study, we examined that it might be involved in a feedback loop controlling cell ZAC expression in normal skin and found a high proliferation on mitogen activation (5). In addition to its role as expression level in basal keratinocytes and a lower, a transcription factor, Zac1 serves as a transcriptional more heterogeneous, expression in the first suprabasal coactivator or corepressor of nuclear receptors and binds to differentiating layers of epidermis. In vitro, ZAC was the nuclear receptor coactivators CBP/p300 and p160 (6). More up-regulated following induction of keratinocyte recently, it was suggested that Zac1 is a transcriptional differentiation. Conversely, ZAC expression triggered coactivator for p53 (7) and that it regulates the proapoptotic keratinocyte differentiation as indicated by induction of gene Apaf-1 (8). involucrin expression. Interestingly, we found a dramatic The human orthologue ZAC/LOT1/PLAGL1 is widely loss of ZAC expression in basal cell carcinoma, a expressed in normal tissues and the corresponding protein neoplasm characterized by a relatively undifferentiated binds DNA and displays transactivation activity (9). As its morphology. In contrast, ZAC expression was mouse counterpart, human ZAC displays an antiproliferative maintained in squamous cell carcinomas that retain activity by inducing apoptosis and cell cycle arrest in the squamous differentiated phenotype. Altogether, transfected cells. In addition, alternative splicing of human these data suggest a role for ZAC at an early stage of ZAC transcript generates two mRNA species encoding proteins keratinocyte differentiation and further support its role in with different number of zinc finger domains (5 versus 7), carcinogenesis. (Mol Cancer Res 2005;3(9):483–92) which differentially regulate apoptosis and cell cycle arrest (10). Noteworthy, ZAC maps to chromosome 6q24-q25 (9, 11), Introduction a region frequently deleted in many solid tumors and thought Zac1 is a mouse zinc finger transcription factor, which to harbor at least one tumor suppressor gene. Loss of induces apoptosis and cell cycle arrest in vitro, and abrogates heterozygosity at 6q24-q25 occurs in breast and ovary cancer, tumor formation in nude mice (1). Zac1 binds DNA and melanomas, astrocytomas, and renal cell carcinomas. The functional properties of ZAC and the chromosomal location of the corresponding gene make it a plausible candidate for the tumor suppressor gene at 6q24-q25. Received 2/22/05; revised 8/5/05; accepted 8/11/05. Grant support: Centre National de la Recherche Scientifique, La Ligue In this context, loss or down-regulation of ZAC expression is Nationale contre le Cancer, and L’Association pour la Recherche contre le observed in a large proportion of mammary (12) and ovary Cancer (A. Gandarillas and L. Journot), La Ligue Nationale contre le Cancer (11, 13) tumor-derived cell lines and tumors, in nonfunctioning fellowship (V. Coulon), and European Molecular Biology Organization fellowship (A. Gandarillas). pituitary adenomas (14), and in head and neck squamous cell The costs of publication of this article were defrayed in part by the payment of carcinoma (SCC; ref. 15). Expression profiling of human breast page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. tumors (16), lung adenocarcinomas (17), and breast tumor– Requests for reprints: Laurent Journot, Institut de Ge´nomique Fonctionnelle, derived cell lines (16, 18) with microarrays confirmed down- 141, rue de la cardonille, F-34094 Montpellier Cedex 5, France. Phone: 33-467- regulation of ZAC expression. We found that ZAC expression is 142-932; Fax: 33-467-542-432. E-mail: [email protected] Copyright D 2005 American Association for Cancer Research. reinduced in breast tumor–derived cell lines by treatment with doi:10.1158/1541-7786.MCR-05-0019 the demethylating agent azacytidine, suggesting that the Mol Cancer Res 2005;3(9). September 2005 483 Downloaded from mcr.aacrjournals.org on September 29, 2021. © 2005 American Association for Cancer Research. 484 Basyuk et al. methylation status of ZAC gene critically modulates its and two common types of nonmelanoma skin cancer [i.e., expression (12). This hypothesis was further supported by the basal cell carcinomas (BCC) and SCCs]. Our data suggest a demonstration of ZAC imprinting in human (19, 20) and mice role for ZAC in keratinocyte differentiation and BCC (21) and by the finding that methylation of ZAC promoter is formation. responsible for its observed monoallelic expression (22, 23). Although the above-mentioned data support a role for ZAC as a Results tumor suppressor gene, its precise mechanism of action and ZAC Expression in Normal Skin target genes are mostly unknown at present. We first examined ZAC expression in five normal human Because ZAC is potentially involved in the homeostasis of skin samples using nonradioactive in situ hybridization with mammary and ovary epithelial cells, we assessed its digoxigenin-labeled riboprobes. As a positive control for in situ expression in different epithelial tissues, including epidermis. hybridization, we used a probe for the differentiation marker Human epidermis is a stratified, constantly renewed epithelium cytokeratin K1, which prominently labeled the suprabasal in which proliferation and differentiation are compartmental- spinous layers of epidermis and, to a lesser extent, the granular ized and tightly controlled. It consists of basal, suprabasal layer but not the basal layer (Fig. 1A). As a negative control, (lower spinous, upper spinous, and granular), and cornified identical samples were hybridized with a probe for lacZ that layers. The basal layer comprises two populations of produced no signal (Fig. 1B). In situ hybridization with the keratinocytes: stem cells and transit amplifying cells that ZAC probe showed a strong and homogenous expression in initiated their differentiation program after a rapid phase of the basal layer of epidermis (Fig. 1C and D). We detected as clonal expansion (24, 25). Differentiating keratinocytes detach well a faint and more heterogeneous expression in the spinous from the basal membrane, increase in size, and transform into layers. Interestingly, in one normal skin sample, we detected a cornified envelope that sheds from the surface of the skin ZAC expression in all suprabasal keratinocytes, including the (26). Therefore, the epidermis is an excellent model to study lower and upper spinous and granular layers (data not shown), the regulation of proliferation and differentiation in vivo and indicative of some individual variations. We also observed ZAC its alteration during carcinogenesis. expression in the dermal fibroblasts (Fig. 1D) and in the In the present study, we analyzed ZAC expression during epithelial cells of the sudoriferous glands (Fig. 1E). In contrast, differentiation of human primary keratinocytes in vitro and no expression was observed in the endothelium of the blood in normal and pathologic skin samples, including psoriasis vessels (Fig. 1F). FIGURE 1. ZAC expression in normal skin. Sections from normal skin samples were processed for in situ hybridization with probes for cytokeratin 1 (A), h-galactosidase (B), or ZAC (C-F). A-D. Epidermis. E. Sudoriferous gland. F. Blood vessel. A, B, and D-F. The field is 1.5 Â 1.2 mm. C. The field is 3 Â 2.4 mm. Mol Cancer Res 2005;3(9). September 2005 Downloaded from mcr.aacrjournals.org on September 29, 2021. © 2005 American Association for Cancer Research. ZAC Is Involved in Keratinocyte Differentiation 485 ZAC Expression Is Induced in Early Differentiating Keratinocytes In vitro To gain insights into the role of ZAC in epithelial cell biology, we analyzed ZAC expression during keratinocyte differentiation in vitro. Primary culture of human keratinocytes is widely used to study factors that regulate stem cell proliferation, the initiation of terminal
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