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J Mol Med (2014) 92:571581 DOI 10.1007/s00109-014-1160-3
REVIEW
ZNF281/ZBP-99: a new player in epithelialmesenchymal transition, stemness, and cancer
Stefanie Hahn & Heiko Hermeking
Received: 4 February 2014 /Revised: 4 March 2014 /Accepted: 25 April 2014 /Published online: 18 May 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract Epithelialmesenchymal transition (EMT) represents an important mechanism during development and wound healing, and its deregulation has been implicated in metastasis. Recently, the Krppel-type zinc-finger transcription factor ZNF281 has been characterized as an EMT-inducing transcription factor (EMT-TF). Expression of ZNF281 is induced by the EMT-TF SNAIL and inhibited by the tumor suppressive microRNA miR-34a, which mediates repression of ZNF281 by the p53 tumor suppressor. Therefore, SNAIL, miR-34a and ZNF281 form a feed-forward regulatory loop, which controls EMT. Deregulation of this circuitry by mutational and epigenetic alterations in the p53/ miR-34a axis promotes colorectal cancer (CRC) progression and metastasis formation. As ZNF281 physically interacts with the transcription factors NANOG, OCT4, SOX2, and c-MYC, it has been implicated in the regulation of pluripotency, stemness, and cancer. Accordingly, ectopic ZNF281 expression in CRC lines induces the stemness markers LGR5 and CD133 and promotes sphere formation, suggesting that the elevated expression of ZNF281 detected in cancer may enhance tumor stem cell formation and/or function. Here, we review the functional and organismal studies of ZNF281/ ZBP-99 and its close relative ZBP-89/ZFP148 reported so far. Taken together, ZNF281 related biology has the potential
to be translated into cancer diagnostic, prognostic, and therapeutic approaches.
Keywords Cancer .EMT .Metastasis .miR-34a .Stemness . ZNF281/ZBP-99
Introduction
Here, we address the role of the transcription factor ZNF281/ ZBP-89, which has been largely neglected in cancer and developmental biology research so far. However, recently several genome and proteome wide, as well as functional studies have shed new light on the role and function of ZNF281. Interestingly, these studies link ZNF281 to the regulation of stem cell factors, epithelialmesenchymal transition (EMT) and the WNT pathway. Taken together, they suggest that ZNF281 may play a role during carcinogenesis.
ZNF281/ZBP-99: a zinc-finger transcription factor
The ZNF281/ZBP-99 protein has first been identified less than 15 years ago in a yeast one-hybrid screen for proteins that bind to GC-rich sequences and was therefore first named GC-box-binding zinc-finger protein (GZP1) [1]. The ZNF281 gene is phylogenetically conserved among...