ZNF281/ZBP-99: a new player in epithelial–mesenchymal transition, stemness, and cancer

Epithelial–mesenchymal transition (EMT) represents an important mechanism during development and wound healing, and its deregulation has been implicated in metastasis. Recently, the Krüppel-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.