Metastatic tumor antigen 3 is a direct corepressor of the Wnt4 pathway.
Here we show that expression of MTA3 inhibits ductal branching in virgin and pregnant murine transgenic mammary glands. MTA3 also suppresses the Wnt4 pathway and, thus, these findings parallel phenotypic changes in Wnt4-null mice. MTA3 represses Wnt4 transcription and Wnt4 secretion, inhibiting Wnt-target genes in mammary epithelial cells. Accordingly, knockdown of endogenous MTA3 stimulates Wnt4 expression and Wnt cellular targets. The MTA3-NuRD (nucleosome remodeling and deacetylase) complex physically interacts with the Wnt4 chromatin in an HDAC-dependent manner, leading to suppression of the Wnt4 gene and Wnt4-dependent morphogenesis. These findings identify MTA3 as an upstream physiologic repressor of Wnt4 in mammary epithelial cells.
Zhang
Hao
H
Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Singh
Rajesh R
RR
Talukder
Amjad H
AH
Kumar
Rakesh
R
D000818:Animals; D002843:Chromatin / Q000378:metabolism; D015536:Down-Regulation; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008321:Mammary Glands, Animal / Q000002:abnormalities / Q000254:growth & development* / Q000378:metabolism; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex; D051379:Mice; D008822:Mice, Transgenic; D009024:Morphogenesis / Q000235:genetics*; D009363:Neoplasm Proteins / Q000378:metabolism*; D011247:Pregnancy; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction; D051153:Wnt Proteins / Q000235:genetics*; D060528:Wnt4 Protein
D002843:Chromatin; C486657:MTA3 protein, human; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; C555581:WNT4 protein, human; D051153:Wnt Proteins; D060528:Wnt4 Protein; C555582:Wnt4 protein, mouse; D006655:Histone Deacetylases; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex