RNF208, an estrogen-inducible E3 ligase, targets soluble Vimentin to suppress metastasis in triple-negative breast cancers

Kyoungwha Pang, Jinah Park, Sung Gwe Ahn, Jihee Lee, Yuna Park, Akira Ooshima, Seiya Mizuno, Satoshi Yamashita, Kyung-Soon Park, So-Young Lee, Joon Jeong, Toshikazu Ushijima, Kyung-Min Yang () and Seong-Jin Kim ()
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Kyoungwha Pang: Seoul National University
Jinah Park: Seoul National University
Sung Gwe Ahn: Yonsei University Medical College
Jihee Lee: Seoul National University
Yuna Park: Seoul National University
Akira Ooshima: Seoul National University
Seiya Mizuno: University of Tsukuba
Satoshi Yamashita: National Cancer Center Research Institute
Kyung-Soon Park: CHA University
So-Young Lee: CHA University
Joon Jeong: Yonsei University Medical College
Toshikazu Ushijima: National Cancer Center Research Institute
Kyung-Min Yang: Seoul National University
Seong-Jin Kim: Seoul National University

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: Abstract The development of triple-negative breast cancer (TNBC) negatively impacts both quality of life and survival in a high percentage of patients. Here, we show that RING finger protein 208 (RNF208) decreases the stability of soluble Vimentin protein through a polyubiquitin-mediated proteasomal degradation pathway, thereby suppressing metastasis of TNBC cells. RNF208 was significantly lower in TNBC than the luminal type, and low expression of RNF208 was strongly associated with poor clinical outcomes. Furthermore, RNF208 was induced by 17β-estradiol (E2) treatment in an estrogen receptor alpha (ΕRα)-dependent manner. Overexpression of RNF208 suppresses tumor formation and lung metastasis of TNBC cells. Mechanistically, RNF208 specifically polyubiquitinated the Lys97 residue within the head domain of Vimentin through interaction with the Ser39 residue of phosphorylated Vimentin, which exists as a soluble form, eventually facilitating proteasomal degradation of Vimentin. Collectively, our findings define RNF208 as a negative regulator of soluble Vimentin and a prognostic biomarker for TNBC cells.

Date: 2019
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DOI: 10.1038/s41467-019-13852-5

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