Abstract LB-137: YAP promotes breast cell proliferation and survival partially through stabilizing the KLF5 transcription factor

Abstract

Abstract The Yes-associated protein (YAP) is an oncoprotein in the Hippo tumor suppressor pathway that regulates tumorigenesis. Although YAP functions through its WW domains, the YAP WW domain binding partners have not been completely determined. In this study, we demonstrate that YAP functions partially through binding to KLF5, a transcription factor promoting breast cell proliferation and survival. YAP interacts with the KLF5 PY motif through its WW domains, prevents WWP1, a KLF5 E3 ubiquitin ligase, from binding to KLF5, and stabilizes KLF5 by decreasing the WWP1-mediated KLF5 ubiquitination and degradation. Over-expression of the wild type but not WW domain deficient YAP up-regulates the KLF5 protein levels and the mRNA expression levels of the KLF5 downstream target genes, including FGF-BP and ITGB2. In addition, knockdown of YAP decreases the expression levels of KLF5, FGF-BP, and ITGB2. Depletion of either YAP or KLF5 decreases breast cell proliferation and survival in MCF10A and SW527 breast cells. Importantly, stable knockdown of YAP or KLF5 significantly suppresses SW527 xenograft growth in mice. The YAP upstream kinase LATS1 suppresses the KLF5-FGF-BP signaling axis and cell growth through YAP. Finally, both YAP and KLF5 are co-expressed in estrogen receptor (ERα)-negative breast cell lines. These findings suggest that KLF5 is an important transcription factor partner for YAP and contributes to the Hippo tumor suppressor pathway. 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-137. doi:10.1158/1538-7445.AM2011-LB-137