Jin Yue, Shenoy Anitha K, Doernberg Samuel, Chen Hao, Luo Huacheng, Shen Huangxuan, Lin Tong, Tarrash Miriam, Cai Qingsong, Hu Xin, Fiske Ryan, Chen Ting, Wu Lizi, Mohammed Kamal A, Rottiers Veerle, Lee Siu Sylvia, Lu Jianrong
Department of Biochemistry and Molecular Biology, University of Florida College of Medicine Gainesville, FL 32610, USA; College of Life Science, Jilin University, Changchun, 130023, China.
Department of Biochemistry and Molecular Biology, University of Florida College of Medicine Gainesville, FL 32610, USA.
Cancer Lett. 2015 Jun 28;362(1):70-82. doi: 10.1016/j.canlet.2015.03.037. Epub 2015 Mar 28.
The Snail family of transcription factors are core inducers of epithelial-to-mesenchymal transition (EMT). Here we show that the F-box protein FBXO11 recognizes and promotes ubiquitin-mediated degradation of multiple Snail family members including Scratch. The association between FBXO11 and Snai1 in vitro is independent of Snai1 phosphorylation. Overexpression of FBXO11 in mesenchymal cells reduces Snail protein abundance and cellular invasiveness. Conversely, depletion of endogenous FBXO11 in epithelial cancer cells causes Snail protein accumulation, EMT, and tumor invasion, as well as loss of estrogen receptor expression in breast cancer cells. Expression of FBXO11 is downregulated by EMT-inducing signals TGFβ and nickel. In human cancer, high FBXO11 levels correlate with expression of epithelial markers and favorable prognosis. The results suggest that FBXO11 sustains the epithelial state and inhibits cancer progression. Inactivation of FBXO11 in mice leads to neonatal lethality, epidermal thickening, and increased Snail protein levels in epidermis, validating that FBXO11 is a physiological ubiquitin ligase of Snail. Moreover, in C. elegans, the FBXO11 mutant phenotype is attributed to the Snail factors as it is suppressed by inactivation/depletion of Snail homologs. Collectively, these findings suggest that the FBXO11-Snail regulatory axis is evolutionarily conserved and critically governs carcinoma progression and mammalian epidermal development.
转录因子Snail家族是上皮-间质转化（EMT）的核心诱导因子。在此我们表明，F-box蛋白FBXO11识别并促进包括Scratch在内的多个Snail家族成员的泛素介导降解。FBXO11与Snai1在体外的结合不依赖于Snai1的磷酸化。在间充质细胞中过表达FBXO11可降低Snail蛋白丰度和细胞侵袭性。相反，上皮癌细胞中内源性FBXO11的缺失会导致Snail蛋白积累、EMT和肿瘤侵袭，以及乳腺癌细胞中雌激素受体表达的丧失。EMT诱导信号TGFβ和镍可下调FBXO11的表达。在人类癌症中，高FBXO11水平与上皮标志物的表达及良好预后相关。结果表明，FBXO11维持上皮状态并抑制癌症进展。小鼠中FBXO11的失活导致新生儿死亡、表皮增厚以及表皮中Snail蛋白水平升高，证实FBXO11是Snail的生理性泛素连接酶。此外，在秀丽隐杆线虫中，FBXO11突变体表型归因于Snail因子，因为它可被Snail同源物的失活/缺失所抑制。总体而言，这些发现表明FBXO11-Snail调节轴在进化上是保守的，并且对癌症进展和哺乳动物表皮发育起着关键的调控作用。
