Roles of N-Myc and STAT interactor in cancer: From initiation to dissemination

Pruitt, Hawley C.; Devine, Daniel J.; Samant, Rajeev S.

o-receptor and the FZD7 receptor, upregulation of secreted Wnt ligands and silencing of Wnt inhibitors SFRP-1 and WIF1. 54 In agreement with the findings that NMI inhibits EMT, NMI has also been shown to attenuate Wnt signaling, one of the pathways that can promote EMT. Stably expressing NMI in MDA-MB-231 and MDA-MB-435 cancer cell lines led to increased levels of DKK1 and concomitantly reduced levels of b-catenin and c-Myc, known downstream targets of Wnt signaling. 55 DKK1 is a secreted inhibitor of Wnt signaling that has been shown to restrict tumor growth in breast cancer. 56 In the same study, stably expressing NMI reduced tumor growth in vitro and in vivo, as well as invasion and migration of tumor cells. 55 In addition to its effect on DKK1, NMI has the potential to influence Wnt signaling through its interaction with Casein kinase 2 interacting protein-1 (CKIP1 or PLEKHO1). 57 CKIP1 interacts with the catalytic subunit of casein kinase 2 (CK2a) through its pleckstrin homology domain. 58 CK2a phosphorylates and inhibits Dishevelled, a negative regulator of Wnt signaling, and also phosphorylates and stabilizes b-catenin. 59 This ultimately enhances the transcription of Wnt target genes. How CKIP1 affects CK2a, and whether its interaction with NMI directly influences Wnt signaling, are questions that remain unanswered.