α-Parvin promotes breast cancer progression and metastasis through interaction with G3BP2 and regulation of TWIST1 signaling.
α-Parvin promotes breast cancer progression and metastasis through interaction with G3BP2 and regulation of TWIST1 signaling.
复制标题
α-Parvin 通过与 G3BP2 相互作用和调节 TWIST1 信号传导促进乳腺癌进展和转移
DOI：
10.1038/s41388-019-0762-1
复制
发表时间：
2019
期刊：
影响因子：
8
通讯作者：
Wu Chuanyue
中科院分区：
文献类型：
--
作者：
Sun Ying;Ding Yanyan;Guo Chen;Liu Chengmin;Ma Ping;Ma Shuang;Wang Zhe;Liu Jie;Qian Tao;Ma Luyao;Deng Yi;Wu Chuanyue
识别驱动乳腺癌进展的分子改变对于开发有效治疗至关重要。在这项研究中，我们发现α-parvinis的水平在三阴性乳腺癌细胞中升高。从三阴性乳腺癌细胞中去除α-parvin在体外有效地抑制乳腺癌细胞的生长、迁移和侵袭，在体内有效地抑制肿瘤的进展和转移。在分子水平上，我们鉴定了Ras-GTP酶激活蛋白SH 3结构域结合蛋白2（G3 BP 2）作为α-parvin结合蛋白。α-parvin的敲低促进了G3 BP 2与TWIST 1的相互作用，增加了TWIST 1的泛素化和蛋白酶体依赖性降解，从而降低了TWIST 1及其下游信号转导的细胞水平。重要的是，G3 BP 2的缺失逆转了TWIST 1水平和信号传导的降低以及α-parvin缺失诱导的乳腺癌进展的抑制。此外，与野生型α-parvin不同，在α-parvin缺陷型乳腺癌细胞中，G3 BP 2结合位点被消除的α-parvin突变体的再表达不能恢复TWIST 1的水平和信号传导并促进乳腺癌进展。最后，我们发现在人类三阴性乳腺癌患者中α-parvinis的蛋白水平与TWIST 1的蛋白水平高度正相关。我们的研究揭示了一种由α-parvin、G3 BP 2和TWIST 1组成的调节乳腺癌进展和转移的新型信号通路，并表明该信号通路的激活是驱动人类ER阴性乳腺癌进展和不良临床结局的关键因素。
Identification of molecular alterations driving breast cancer progression is critical for the development of effective therapy. In this study, we show that the level ofα-parvinis elevated in triple-negative breast cancer cells. The depletion ofα-parvinfrom triple-negative breast cancer cells effectively inhibits breast cancer cell growth, migration, and invasion in vitro, and tumor progression and metastasis in vivo. At the molecular level, we identify Ras-GTPase-activing protein SH3-domain-binding protein 2 (G3BP2) as anα-parvin-binding protein. Knockdown ofα-parvinpromotes G3BP2 interaction with TWIST1, increases ubiquitination and proteasome-dependent degradation of TWIST1, and consequently reduces the cellular level of TWIST1 and its downstream signaling. Importantly, the depletion of G3BP2 reverses the reduction in the level and signaling of TWIST1 and the suppression of breast cancer progression induced by the loss ofα-parvin. Furthermore, the re-expression of anα-parvinmutant in which the G3BP2-binding site is ablated, unlike that of wild-typeα-parvin, inα-parvin-deficient breast cancer cells, is unable to restore the level and signaling of TWIST1 and promote breast cancer progression. Finally, we show that protein level ofα-parvinis highly positively correlated with that of TWIST1 in human triple-negative breast cancer patients. Our studies reveal a novel signaling pathway consisting ofα-parvin, G3BP2, and TWIST1 that regulates breast cancer progression and metastasis, and suggest that the activation of this signaling pathway is a key factor for driving the progression and poor clinical outcome of human ER-negative breast cancer.