Nmi (N-Myc interactor) inhibits Wnt/beta-catenin signaling and retards tumor growth.
We found that the expression levels of N-Myc interactor (Nmi) were low in aggressive breast cancer cell lines when compared with less aggressive cell lines. However, the lower levels in the aggressive lines were inducible by interferon-gamma (IFN-gamma). Because Nmi has been reported to be a transcription cofactor that augments IFN-gamma induced transcription activity, we decided to test whether Nmi regulates expression of Dkk1, which is also inducible by IFN-gamma. We established stable clones constitutively expressing Nmi in MDA-MB-231 (breast) and MDA-MB-435 (melanoma) cell lines. Dkk1 was significantly up-regulated in the Nmi expressing clones concurrent with reduced levels of the critical transcription cofactor of Wnt pathway, beta-catenin. Treatment of the Nmi expressors with blocking antibody to Dkk1 restored beta-catenin protein levels. c-Myc is a known downstream target of activated beta-catenin signaling. Treatment of Nmi expressors with the proteosome inhibitor MG132, resulted in elevated beta-catenin levels with concomitant elevation of c-Myc levels. Our functional studies showed that constitutive expression of Nmi reduced the ability of tumor cells for the invasion, anchorage independent growth and tumor growth in vivo. Collectively, the data suggest that overexpression of Nmi inhibits the Wnt/beta-catenin signaling via up-regulation of Dkk1 and retards tumor growth.
Fillmore
Rebecca A
RA
Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA.
Mitra
Aparna
A
Xi
Yaguang
Y
Ju
Jingfang
J
Scammell
Jonathan
J
Shevde
Lalita A
LA
Samant
Rajeev S
RS
D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015151:Immunoblotting; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D010957:Plasmids; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
C501126:DKK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; C099927:NMI protein, human; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D051153:Wnt Proteins; D051176:beta Catenin