USP1 Regulates TAZ Protein Stability Through Ubiquitin Modifications in Breast Cancer.
USP1 Regulates TAZ Protein Stability Through Ubiquitin Modifications in Breast Cancer.
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USP1通过乳腺癌中的泛素修饰来调节TAZ蛋白稳定性。
DOI：
10.3390/cancers12113090
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发表时间：
2020-10-23
期刊：
影响因子：
5.2
通讯作者：
Zhang J
中科院分区：
文献类型：
--
作者：
Mussell A;Shen H;Chen Y;Mastri M;Eng KH;Bshara W;Frangou C;Zhang J
三阴性乳腺癌(TNBC)是女性中最具侵袭性的乳腺癌。严重缺乏治疗这种疾病的有针对性的疗法。通过对河马信号通路的关键成分-带有PDZ结合基序的转录共激活因子(TAZ)的机制研究，我们的目标是发现新的调控因子，可能被用作该疾病的靶向治疗。通过siRNA靶向脱泛素酶的筛选，我们鉴定了泛素特异肽酶1(USP1)是一种新的TAZ脱泛素酶。我们发现USP1与TAZ相互作用，USP1的缺失以部分依赖于TAZ的方式抑制细胞增殖。此外，我们还证明USP1和TAZ在TNBC患者中的表达呈正相关。本研究发现了一种新定义的TAZ的调节机制，可用于乳腺癌的治疗。河马信号通路是一种进化上保守的通路，最初在果蝇中发现，后来发现与哺乳动物有同源基因。这一途径中的关键效应蛋白YAP/TAZ在癌症中经常处于失调状态，导致细胞高度增殖、迁移、转移和肿瘤干细胞群。鉴于这些恶性表型，在蛋白质水平上了解YAP/TAZ的调控是很重要的。利用脱泛素化酶(DUBS)的siRNA文库筛选，我们鉴定了泛素特异肽酶1(USP1)是一种新的TAZ(WWTR1)调节因子。我们证明了USP1与TAZ相互作用，并增加了TAZ蛋白的稳定性。相反，USP1功能的丧失通过增加多泛素化来降低TAZ蛋白水平，导致乳腺癌细胞的细胞增殖和迁移减少。此外，在乳腺癌患者中，USP1与TAZ呈显著正相关。我们的发现有助于更好地了解这些通路之间的串扰，并可能为乳腺癌患者提供潜在的治疗干预措施。
Triple-Negative breast cancer (TNBC) is the most aggressive form of breast cancer in women. Targeted therapies for the treatment of this disease are severely lacking. Through mechanistic studies of the key component of Hippo signaling pathway, Transcriptional co-activator with PDZ-binding motif (TAZ), we aimed to uncover novel regulators that may be used as targeted therapies for this disease. Using an siRNA target deubiquitinating enzymes screen, we identified ubiquitin-specific peptidase 1 (USP1) as a novel TAZ deubiquitinating enzyme. We found that USP1 interacts with TAZ and loss of USP1 reduces cell proliferation in a partially TAZ-dependent manner. Furthermore, we demonstrated that USP1 and TAZ expression are positively correlated in TNBC patients. This research found a newly defined regulatory mechanism of TAZ that could be used as a therapeutic approach for breast cancer. The Hippo signaling pathway is an evolutionarily conserved pathway that was initially discovered in Drosophila melanogaster and was later found to have mammalian orthologues. The key effector proteins in this pathway, YAP/TAZ, are often dysregulated in cancer, leading to a high degree of cell proliferation, migration, metastasis and cancer stem cell populations. Due to these malignant phenotypes it is important to understand the regulation of YAP/TAZ at the protein level. Using an siRNA library screen of deubiquitinating enzymes (DUBs), we identified ubiquitin specific peptidase 1 (USP1) as a novel TAZ (WWTR1) regulator. We demonstrated that USP1 interacts with TAZ and increases TAZ protein stability. Conversely, loss of function of USP1 reduces TAZ protein levels through increased poly-ubiquitination, causing a decrease in cell proliferation and migration of breast cancer cells. Moreover, we showed a strong positive correlation between USP1 and TAZ in breast cancer patients. Our findings facilitate the attainment of better understanding of the crosstalk between these pathways and may lead to potential therapeutic interventions for breast cancer patients.
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影响因子：
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作者：
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通讯作者：
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DOI：
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16.6
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DOI：
10.1186/s13046-018-0912-2
发表时间：
2018-09-27
期刊：
Journal of experimental & clinical cancer research : CR
影响因子：
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