UBE2O promotes the proliferation, EMT and stemness properties of breast cancer cells through the UBE2O/AMPKα2/mTORC1-MYC positive feedback loop.,Cell Death & Disease

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UBE2O promotes the proliferation, EMT and stemness properties of breast cancer cells through the UBE2O/AMPKα2/mTORC1-MYC positive feedback loop.
Cell Death & Disease ( IF 8.1 ) Pub Date : 2020-01-06 , DOI: 10.1038/s41419-019-2194-9
Xu Liu ₁ , Fei Ma ₁ , Chunxiao Liu ₁ , Kaiyuan Zhu ₁ , Wenjie Li ₁ , Yuting Xu ₁ , Ge Li ₁ , Zhenbo Niu ₁ , Jiaxin Liu ₁ , Du Chen ₁ , Zhigao Li ₁ , Yingqiang Fu ₁ , Cheng Qian _{1,

2}

Affiliation

Ubiquitin-conjugating enzyme E2O (UBE2O) is a large E2 ubiquitin-conjugating enzyme that possesses both E2 and E3 ligase activities. Ectopic UBE2O overexpression is associated with a variety of human diseases, especially cancers. However, the expression profile and functional biology of UBE2O in human breast cancer (BC) remain unclear. In this study, we found that UBE2O was significantly overexpressed in human BC tissues and cells. Patients with high UBE2O expression tended to have a high risk of metastasis and poor prognosis. In vitro assays revealed that UBE2O promoted BC cell proliferation and epithelial-mesenchymal transformation (EMT) and endowed BC cells with cancer stemness properties (CSPs). UBE2O knockdown in MDA-MB-231 cells suppressed tumour growth and lung metastasis in MDA-MB-231 xenograft mouse models. Mechanistically, UBE2O functioned as a ubiquitin enzyme of AMPKα2, promoting its ubiquitination and degradation and thus activating the mTORC1 signal pathway and contributing to BC oncogenesis and metastasis. Furthermore, as a downstream factor of the UBE2O/AMPKα2/mTORC1 axis, the oncoprotein MYC transcriptionally promoted UBE2O and formed a positive feedback loop in human BC. Collectively, our study demonstrated that UBE2O/AMPKα2/mTORC1-MYC forms a positive feedback loop in human BC cells that regulates BC cell proliferation and EMT and endows BC cells with CSPs.

中文翻译：

UBE2O通过UBE2O /AMPKα2/ mTORC1-MYC正反馈回路促进乳腺癌细胞的增殖，EMT和干性。

泛素结合酶E2O（UBE2O）是一种大型的E2泛素结合酶，具有E2和E3连接酶活性。异位UBE2O过度表达与多种人类疾病，尤其是癌症有关。但是，UBE2O在人乳腺癌（BC）中的表达谱和功能生物学尚不清楚。在这项研究中，我们发现UBE2O在人BC组织和细胞中明显过表达。UBE2O表达高的患者倾向于转移的风险高，预后差。体外测定显示，UBE2O促进BC细胞增殖和上皮-间质转化（EMT），并使BC细胞具有癌干特性（CSP）。在MDA-MB-231异种移植小鼠模型中，MDA-MB-231细胞中的UBE2O敲低抑制了肿瘤生长和肺转移。机械上，UBE2O充当AMPKα2的泛素酶，促进其泛素化和降解，从而激活mTORC1信号通路，并促进BC肿瘤的发生和转移。此外，作为UBE2O /AMPKα2/ mTORC1轴的下游因子，癌蛋白MYC转录促进UBE2O并在人BC中形成正反馈环。总体而言，我们的研究表明，UBE2O /AMPKα2/ mTORC1-MYC在人BC细胞中形成正反馈回路，调节BC细胞增殖和EMT，并使BC细胞具有CSP。癌蛋白MYC转录促进UBE2O并在人BC中形成正反馈环。总体而言，我们的研究表明，UBE2O /AMPKα2/ mTORC1-MYC在人BC细胞中形成正反馈回路，调节BC细胞增殖和EMT，并使BC细胞具有CSP。癌蛋白MYC转录促进UBE2O并在人BC中形成正反馈环。总体而言，我们的研究表明，UBE2O /AMPKα2/ mTORC1-MYC在人BC细胞中形成正反馈回路，调节BC细胞增殖和EMT，并使BC细胞具有CSP。

更新日期：2020-01-06

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