Metastatic tumor antigen 3 is a direct corepressor of the Wnt4 pathway (original) (raw)

  1. Hao Zhang1,3,
  2. Rajesh R. Singh1,3,
  3. Amjad H. Talukder1,3, and
  4. Rakesh Kumar1,2,4
  5. 1Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA;
  6. 2Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA
  7. ↵3 These authors contributed equally to this work.

Abstract

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.

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