近日,，國際癌癥領(lǐng)域主流雜志Carcinogenesis刊登了中國科學(xué)院昆明動(dòng)物研究所研究人員的最新研究成果“TAZ antagonizes the WWP1-mediated KLF5 degradation and promotes breast cell proliferation and tumorigenesis,。”文章中，研究人員首次證實(shí)了TAZ促進(jìn)乳腺細(xì)胞的增生機(jī)制是部分通過保護(hù)KLF5免受WWP1介導(dǎo)的泛素化降解,。
乳腺癌是女性最常見的惡性腫瘤之一，雌激素受體ER,、孕激素受體PR和表皮生長(zhǎng)因子受體HER2均為陰性的（簡(jiǎn)稱三陰性）乳腺癌是預(yù)后最差的一類,，目前沒有有效的靶向治療藥物，對(duì)放射治療和化療也不敏感,，因此尋找三陰性乳腺癌的有效治療靶點(diǎn)是目前研究的熱點(diǎn)之一,。中國科學(xué)院昆明動(dòng)物研究所腫瘤生物學(xué)實(shí)驗(yàn)室陳策實(shí)研究員領(lǐng)導(dǎo)的學(xué)科組前期研究顯示KLF5轉(zhuǎn)錄因子在一部分三陰性的乳腺癌中特異高表達(dá)，KLF5通過緊密控制FGF-BP癌基因表達(dá)促進(jìn)細(xì)胞增殖,、生存以及腫瘤生長(zhǎng),，WWP1 E3泛素連接酶促進(jìn)KLF5蛋白的降解并抑制其功能，但是KLF5的正向調(diào)控機(jī)制尚不清楚,。
最近,，中國科學(xué)院昆明動(dòng)物研究所腫瘤生物學(xué)實(shí)驗(yàn)室陳策實(shí)研究員博士后趙東等人，通過一系列實(shí)驗(yàn)研究發(fā)現(xiàn),， Hippo腫瘤抑制信號(hào)途徑的TAZ（transcriptional co-activator with a PDZ-binding motif）癌蛋白通過其WW結(jié)構(gòu)域結(jié)合KLF5的PPXY序列,，拮抗WWP1 介導(dǎo)的KLF5的蛋白降解，促進(jìn)KLF5的下游基因表達(dá),、細(xì)胞增殖以及腫瘤生長(zhǎng),。而抑制TAZ的蛋白激酶LATS1可以通過TAZ抑制KLF5的表達(dá)和活性。這項(xiàng)研究首次證實(shí)了TAZ促進(jìn)乳腺細(xì)胞的增生機(jī)制是部分通過保護(hù)KLF5免受WWP1介導(dǎo)的泛素化降解,，從而增強(qiáng)KLF5對(duì)下游癌基因表達(dá)的控制并且促進(jìn)細(xì)胞周期進(jìn)展,。該研究提示KLF5可能是Hippo腫瘤抑制信號(hào)途徑中的關(guān)鍵下游成員,，并且證明KLF5和TAZ可以作為三陰性乳腺癌的潛在治療靶點(diǎn)。
該項(xiàng)研究得到了國家自然科學(xué)基金和云南省高端人才項(xiàng)目支持,。（生物谷Bioon.com）
doi:10.1093/carcin/bgr242
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TAZ antagonizes the WWP1-mediated KLF5 degradation and promotes breast cell proliferation and tumorigenesis
Dong Zhao1,2,†, Xu Zhi1,2,†, Zhongmei Zhou1 and Ceshi Chen1,*
Krüppel-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 ubiquitination by E3 ubiquitin ligases, such as WWP1 and SCFFbw7. In this study, we demonstrated that a transcriptional co-activator with the PDZ binding motif (TAZ) upregulated the KLF5 expression through antagonizing the WWP1-, but not Fbw7-, mediated, KLF5 ubiquitination and degradation. TAZ interacted with KLF5 through the WW domain of TAZ and the PY motif of KLF5, which is the binding site for WWP1. TAZ inhibited WWP1-KLF5 protein interaction and WWP1-mediated KLF5 ubiquitination and degradation in a WW domain dependent manner. 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 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 immunodeficient mice. Knockdown of LATS1, a TAZ upstream inhibitory kinase, up-regulated the protein levels of KLF5 and FGF-BP in 184A1 and promoted cell growth through TAZ. Finally, both KLF5 and TAZ were co-expressed in a subset of estrogen receptor (ERα)-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 KLF5’s activities.
