雌激素受體ER陰性乳腺癌是一種惡性程度比較高的乳腺癌類型,，關于此類乳腺癌的信號通路研究一直是癌癥研究領域長期未曾透徹解決的問題。近年來大量文章證實Hippo信號通路與乳腺細胞的增殖和凋亡有著重要關系,。Hippo信號通路的下游主要通過YAP/TAZ共轉錄因子結合其它轉錄因子調控基因表達來實現(xiàn),，目前普遍認為YAP/TAZ結合的主要轉錄因子是TEADs以及含有PY序列的幾個轉錄因子如Smads、RUNX2,、p73和ErbB4,。但是現(xiàn)有的證據(jù)不足以說明YAP/TAZ是通過這些轉錄因子促進細胞增殖和生存的。
陳策實研究員領導的課題組的研究表明,，促進細胞增殖和生存的干細胞轉錄因子KLF5是TAZ的重要合作伙伴,，TAZ的WW結構域與轉錄因子KLF5的PY序列相結合，拮抗WWP1 介導的KLF5的蛋白降解，從而保護KLF5免受WWP1介導的泛素化降解,，促進KLF5的下游基因表達,、細胞增殖以及腫瘤生長（http：//carcin.oxfordjournals.org/content/early/2011/10/31/carcin.bgr242.short）。這個工作今年早期已經(jīng)發(fā)表在《Carcinogenesis》,。但是YAP是否通過類似的機制行使功能還不清楚,。
最近，昆明動物研究所腫瘤生物學實驗室在陳策實研究員指導下,，研究發(fā)現(xiàn)YAP與KLF5在ER陰性乳腺癌細胞系中共同表達,，YAP的第二個WW結構域和KLF5的PY 序列相結合，保護KLF5被WWP1結合,、泛素化和降解,。從而誘導下游FGF-BP、ITGB2等基因的表達,，最終促進乳腺細胞的增殖,、存活、腫瘤生長,。而抑制YAP活性的上游激酶LATS1也可以因此抑制KLF5-FGF-BP,。重要的是，該研究顯示抑制YAP和KLF5表達可以有效抑制ER陰性乳腺癌在動物體內的生長,，提示它們是有效的抗癌藥物靶點,，針對這些新靶點的藥物研發(fā)正在進行之中。
這項研究工作已于近日刊登在了國際癌癥學刊物The American Journal of Pathology上,，而且該研究得到自然科學基金-云南省聯(lián)合重點項目,、云南省高端科技人才項目以及中國科學院百人擇優(yōu)項目資助。（生物谷Bioon.com）
doi:10.1016/j.ajpath.2012.02.025
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YAP Promotes Breast Cell Proliferation and Survival Partially through Stabilizing the KLF5 Transcription Factor
Xu Zhi⁎, †, Dong Zhao⁎, †, Zhongmei Zhou⁎, Rong Liu⁎, Ceshi Chen⁎, ,
The Yes-associated protein (YAP), an oncoprotein in the Hippo tumor suppressor pathway, regulates tumorigenesis and has been found in a variety of tumors, including breast, ovarian, and hepatocellular cancers. Although YAP functions through its WW domains, the YAP WW domain-binding partners have not yet been completely determined. With this study, we demonstrate that YAP functions partially through its binding to KLF5, a transcription factor that promotes breast cell proliferation and survival. YAP interacted with the KLF5 PY motif through its WW domains, preventing the E3 ubiquitin ligase WWP1 from ubiquitinating KLF5. Overexpression of the wild-type YAP but not the WW domain-mutated YAP up-regulated KLF5 protein levels and mRNA expression levels of KLF5 downstream target genes, including FGFBP1 (alias FGF-BP) and ITGB2. In addition, knockdown of YAP decreased expression levels of KLF5, FGF-BP, and ITGB2. Depletion of either YAP or KLF5 decreased breast cell proliferation and survival in MCF10A and SW527 breast cell lines, and stable knockdown of either YAP or KLF5 suppressed SW527 xenograft growth in mice. The YAP upstream kinase LATS1 suppressed the KLF5-FGF-BP axis, as well as cell growth through YAP signaling. Both YAP and KLF5 are coexpressed in estrogen receptor ERα-negative breast cell lines. These findings suggest that KLF5 could be an important transcription factor partner for YAP and may contribute to the Hippo pathway.
