A BTB/POZ protein, NAC-1, is related to tumor recurrence and is essential for tumor growth and survival.
Recent studies have suggested an oncogenic role of the BTB/POZ-domain 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.
Nakayama
Kentaro
K
Department of Pathology, Johns Hopkins Medical Institutions, 1550 Orleans Street, Baltimore, MD 21231, USA.
Nakayama
Naomi
N
Davidson
Ben
B
Sheu
Jim J-C
JJ
Jinawath
Natini
N
Santillan
Antonio
A
Salani
Ritu
R
Bristow
Robert E
RE
Morin
Patrice J
PJ
Kurman
Robert J
RJ
Wang
Tian-Li
TL
Shih
Ie-Ming
IeM
D000818:Animals; D049109:Cell Proliferation; D002470:Cell Survival / Q000502:physiology; D005260:Female; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D009364:Neoplasm Recurrence, Local / Q000209:etiology* / Q000378:metabolism / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D010051:Ovarian Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000473:pathology*; D012097:Repressor Proteins
C516477:NACC1 protein, human; C484605:Nacc1 protein, mouse; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D012097:Repressor Proteins