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

Abstract

ZAC is a zinc finger transcription factor that induces apoptosis and cell cycle arrest in various cell lines. The corresponding gene is maternally imprinted and localized on chromosome 6q24-q25, a region harboring an unidentified tumor suppressor gene for a variety of solid neoplasms. ZAC expression is lost or down-regulated in some breast, ovary, and pituitary tumors and in an in vitro model of ovary epithelial cell transformation. In the present study, we examined ZAC expression in normal skin and found a high expression level in basal keratinocytes and a lower, more heterogeneous, expression in the first suprabasal differentiating layers of epidermis. In vitro, ZAC was up-regulated following induction of keratinocyte differentiation. Conversely, ZAC expression triggered keratinocyte differentiation as indicated by induction of involucrin expression. Interestingly, we found a dramatic loss of ZAC expression in basal cell carcinoma, a neoplasm characterized by a relatively undifferentiated morphology. In contrast, ZAC expression was maintained in squamous cell carcinomas that retain the squamous differentiated phenotype. Altogether, these data suggest a role for ZAC at an early stage of keratinocyte differentiation and further support its role in carcinogenesis. (Mol Cancer Res 2005;3(9):483 -92)

LOT1 (ZAC1/PLAGL1) and its family members: Mechanisms and functions

“…Also, recent data suggested that LOT1 plays a role at an early stage of keratinocyte differentiation and in carcinogenesis (Basyuk et al, 2005). In normal skin, a high expression level of LOT1 was observed in basal keratinocytes and a lower, more heterogeneous, expression in the first suprabasal differentiating layers of epidermis (Basyuk et al, 2005).…”

“…In normal skin, a high expression level of LOT1 was observed in basal keratinocytes and a lower, more heterogeneous, expression in the first suprabasal differentiating layers of epidermis (Basyuk et al, 2005). In vitro, LOT1 was upregulated upon induction of keratinocyte differentiation and was capable of triggering keratinocyte differentiation (Basyuk et al, 2005). LOT1 expression was dramatically lost in basal cell carcinoma, a neoplasm characterized by a relatively undifferentiated morphology; whereas, in squamous cell carcinoma that exhibits differentiated phenotype, LOT1 expression was maintained (Basyuk et al, 2005).…”

“…In vitro, LOT1 was upregulated upon induction of keratinocyte differentiation and was capable of triggering keratinocyte differentiation (Basyuk et al, 2005). LOT1 expression was dramatically lost in basal cell carcinoma, a neoplasm characterized by a relatively undifferentiated morphology; whereas, in squamous cell carcinoma that exhibits differentiated phenotype, LOT1 expression was maintained (Basyuk et al, 2005). With regard to its possible role in pituitary tumorigenesis, a strong reduction or absence of ZAC1/LOT1 mRNA and protein expression was detected in non-functioning pituitary adenomas, while in clinically active pituitary neoplasias, the decrease in ZAC1/LOT1 expression was variable (Pagotto et al, 2000).…”

Multitasking C2H2 Zinc Fingers Link Zac DNA Binding to Coordinated Regulation of p300-Histone Acetyltransferase Activity

“…Expression of Lot1, the rat orthologue of Zac, is lost during spontaneous transformation of ovary surface epithelial cells in vitro (1), and the human orthologue ZAC/ LOT1/PLAGL1, which is widely expressed in normal tissues, is frequently down-regulated in a methylation-sensitive manner in various tumors (4,5).…”

“…Moreover, the almost complete loss in transactivation at low doses of Zac⌬C1 indicates that coordinated binding to the KIX and CH3 domains controls Zac coactivation by p300. The fact that the C1 region and zinc fingers together seemed to regulate coactivation by p300 preferentially at low doses appears pertinent to Zac's biological function regarding rather low protein levels in vivo (4,35,36,49,50). Since Zac-dependent regulation of target genes and antiproliferation demands transactivation (18), we carried out colony formation assays to test whether the differences noted above correlate with Zac's biological activity.…”