A BTB/POZ protein, NAC-1, is related to tumor recurrence and is essential for tumor growth and survival

Abstract

Recent studies have suggested an oncogenic role of the BTB/POZdomain genes in hematopoietic malignancy. The aim of this study is to identify and characterize BTB/POZ-domain genes in the development of human epithelial cancers, i.e., carcinomas. In this study, we focused on ovarian carcinoma and analyzed gene expression levels using the serial analysis of gene expression (SAGE) data in all 130 deduced BTB/POZ genes. Our analysis reveals that NAC-1 is significantly overexpressed in ovarian serous carcinomas and several other types of carcinomas. Immunohistochemistry studies in ovarian serous carcinomas demonstrate that NAC-1 is localized in discrete nuclear bodies (tentatively named NAC-1 bodies), and the levels of NAC-1 expression correlate with tumor recurrence. Furthermore, intense NAC-1 immunoreactivity in primary tumors predicts early recurrence in ovarian cancer. Both coimmunoprecipitation and double immunofluorescence staining demonstrate that NAC-1 molecules homooligomerize through the BTB/POZ domain. Induced expression of the NAC-1 mutant containing only the BTB/POZ domain disrupts NAC-1 bodies, prevents tumor formation, and promotes tumor cell apoptosis in established tumors in a mouse xenograft model. Overexpression of full-length NAC-1 enhanced tumorigenicity of ovarian surface epithelial cells and NIH 3T3 cells in athymic nu/nu mice. In summary, NAC-1 is a tumor recurrence-associated gene with oncogenic potential, and the interaction between BTB/POZ domains of NAC-1 proteins is critical to form the discrete NAC-1 nuclear bodies and essential for tumor cell proliferation and survival.oncogene ͉ ovarian cancer ͉ serial analysis of gene expression

NAC-1 Controls Cell Growth and Survival by Repressing Transcription of Gadd45GIP1, a Candidate Tumor Suppressor

“…NAC-1 is a transcription repressor and is involved in self-renewal and maintenance of pluripotency in embryonic stem cells (16). In human cancer, our previous study reveals that NAC-1 is significantly overexpressed in several types of carcinomas including ovarian serous carcinomas, the most malignant and common type of ovarian cancer (15). The levels of NAC-1 expression correlate with tumor recurrence in ovarian serous carcinomas, and intense NAC-1 immunoreactivity in primary ovarian tumors predicts early recurrence (15).…”

“…Based on analyzing gene expression levels in all 130 deduced human BTB/POZ genes using the serial analysis of gene expression (SAGE) data, we have recently identified NAC-1 as a carcinomaassociated BTB/POZ gene (15). NAC-1 is a transcription repressor and is involved in self-renewal and maintenance of pluripotency in embryonic stem cells (16).…”

KBTBD7, a novel human BTB-kelch protein, activates transcriptional activities of SRE and AP-1

“…Recent studies of BTB family genes suggest their extensive involvement in development and disease. For example, NAC-1 is related to tumor recurrence and is essential for tumor growth and survival (10). KLHL7 antibodies are associated with various cancers, and in some patients also with neurological disease (11).…”

GADD45GIP1 (growth arrest and DNA-damage-inducible, gamma interacting protein 1)

“…The data support the functional role of CRIF1 in prostatic cells (Suh et al, 2008). Using serial analysis of gene expression, NAC1 was found to be significantly overexpressed in ovarian serous carcinomas (Nakayama et al, 2006). Immunohistochemical analysis of ovarian serous carcinomas localized NAC1 to discrete nuclear bodies, and the level of NAC1 expression was found to be correlated with tumor recurrence.…”