Breast cancer metastasis suppressor OTUD1 deubiquitinates SMAD7.
Zhengkui ZhangYao FanFeng XieHang ZhouKe JinLi ShaoWenhao ShiPengfei FangBing YangHans van DamPeter Ten DijkeXiaofeng ZhengXiaohua YanJunling JiaMin ZhengJin JinChen DingSheng YeFangfang ZhouJisheng LiuPublished in: Nature communications (2017)
Metastasis is the main cause of death in cancer patients. TGF-β is pro-metastatic for malignant cancer cells. Here we report a loss-of-function screen in mice with metastasis as readout and identify OTUD1 as a metastasis-repressing factor. OTUD1-silenced cancer cells show mesenchymal and stem-cell-like characteristics. Further investigation reveals that OTUD1 directly deubiquitinates the TGF-β pathway inhibitor SMAD7 and prevents its degradation. Moreover, OTUD1 cleaves Lysine 33-linked poly-ubiquitin chains of SMAD7 Lysine 220, which exposes the SMAD7 PY motif, enabling SMURF2 binding and subsequent TβRI turnover at the cell surface. Importantly, OTUD1 is lost in multiple types of human cancers and loss of OTUD1 increases metastasis in intracardial xenograft and orthotopic transplantation models, and correlates with poor prognosis among breast cancer patients. High levels of OTUD1 inhibit cancer stemness and shut off metastasis. Thus, OTUD1 represses breast cancer metastasis by mitigating TGF-β-induced pro-oncogenic responses via deubiquitination of SMAD7.
Keyphrases
- transforming growth factor
- epithelial mesenchymal transition
- stem cells
- poor prognosis
- endothelial cells
- small cell lung cancer
- long non coding rna
- small molecule
- adipose tissue
- mesenchymal stem cells
- metabolic syndrome
- transcription factor
- amino acid
- stress induced
- postmenopausal women
- diabetic rats
- squamous cell
- single cell