Abstract LB-138: TAZ antagonizes the WWP1-mediated KLF5 degradation and promotes breast cell proliferation

Kruppel-like factor 5 (KLF5) is a PY motif-containing transcription factor promoting breast cell proliferation. The KLF5 protein is rapidly degraded through the proteasome after ubiquitinated by E3 ubiquitin ligases, such as WWP1 and SCF Fbw7 . In this study, we demonstrate that transcriptional co-activator with PDZ binding motif (TAZ) upregulated KLF5 through antagonizing the WWP1-mediated KLF5 ubiquitination and degradation. TAZ interacted with KLF5 through the WW domain and the PY motif, which is the binding site of WWP1. TAZ inhibited WWP1-mediated KLF5 ubiquitination and degradation. Overexpression of TAZ up-regulated the protein levels of KLF5 and FGF-BP, which is a well established KLF5 target gene. In addition, depletion of TAZ in both 184A1 and HCC1937 breast cells dramatically down-regulated protein levels of KLF5 and FGF-BP and inhibited cell growth. Furthermore, stable depletion of either TAZ or KLF5 significantly suppressed HCC1937 xenograft growth in SCID mice. Knockdown of LATS1, a TAZ upstream inhibitory kinase, up-regulated the protein levels of KLF5 and FGF-BP in 184A1 and promoted cell proliferation through TAZ. Finally, both KLF5 and TAZ are co-expressed in a subset of ER-negative breast cell lines. These results, for the first time, suggest that TAZ promotes breast cell growth partially through protecting KLF5 from WWP1-mediated degradation, and enhancing KLF59s activities. This study is supported by a grant from the American Cancer Society (RSG-08–199–01) and a grant from the Department of Defense (W81XWH-07–1–0191). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-138. doi:10.1158/1538-7445.AM2011-LB-138