TMEPAI/PMEPA1 inhibits Wnt signaling by regulating ß-catenin stability and nuclear accumulation in triple negative breast cancer cells.

ABSTRACT

Transmembrane prostate androgen-induced protein (TMEPAI) is a type I transmembrane protein induced by several intracellular signaling pathways such as androgen, TGF-ß, EGF, and Wnt signaling. It has been reported that TMEPAI functions to suppress TGF-ß and androgen signaling but here, we report a novel function of TMEPAI in Wnt signaling suppression. First, we show that TMEPAI significantly inhibits TCF/LEF transcriptional activity stimulated by Wnt3A, LiCl, and ß-catenin. Mechanistically, TMEPAI overexpression prevented ß-catenin accumulation in the nucleus and TMEPAI knockout in triple negative breast cancer cell lines promoted ß-catenin stability and nuclear accumulation together with increased mRNA levels of Wnt target genes AXIN2 and c-MYC. The presence of TGF-ß type I receptor kinase inhibitor did not affect the enhanced mRNA expression of AXIN2 in TMEPAI knockout cells. These data suggest that TMEPAI suppresses Wnt signaling by interfering with ß-catenin stability and nuclear translocation in a TGF-ß signaling-independent manner.