Breast cancer metastasis suppressor OTUD1 deubiquitinates SMAD7.

Abstract

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.

• Authors: Zhengkui Zhang, Yao Fan, Feng Xie, Hang Zhou, Ke Jin, Li Shao, Wenhao Shi, Pengfei Fang, Bing Yang, Hans van Dam, Peter Ten Dijke, Xiaofeng Zheng, Xiaohua Yan, Junling Jia, Min Zheng, Jin Jin, Chen Ding, Sheng Ye, Fangfang Zhou, Long Zhang
• Journal: Nature communications (Nat Commun) Vol. 8 Issue 1 Pg. 2116 (12 13 2017) ISSN: 2041-1723 [Electronic] England
• PMID: 29235476 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Smad7 Protein
• OTUD1 protein, human
• Ubiquitin-Specific Proteases
• Doxycycline

Topics

• Animals
• Breast Neoplasms (drug therapy, genetics, metabolism)
• Cell Line
• Cell Line, Tumor
• Doxycycline (pharmacology)
• Female
• HEK293 Cells
• Humans
• MCF-7 Cells
• Mice, Inbred BALB C
• Mice, Nude
• Neoplasm Metastasis
• RNA Interference
• Smad7 Protein (genetics, metabolism)
• Ubiquitin-Specific Proteases (genetics, metabolism)
• Ubiquitination
• Xenograft Model Antitumor Assays