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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  ;  Seong-Jin Kim 
 NATURE COMMUNICATIONS, Vol.10(1) : e5805, 2019-12 
Journal Title
Issue Date
Animals ; Breast / pathology ; Cell Line, Tumor ; Estradiol / metabolism* ; Estrogen Receptor alpha / metabolism ; Female ; Humans ; Lung / pathology ; Lung Neoplasms / secondary* ; Mice ; Prognosis ; Protein Stability ; Proteolysis ; Survival Analysis ; Tissue Array Analysis ; Triple Negative Breast Neoplasms / mortality ; Triple Negative Breast Neoplasms / pathology* ; Ubiquitin-Protein Ligases / metabolism* ; Ubiquitination ; Vimentin / metabolism* ; Xenograft Model Antitumor Assays
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.
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1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
Yonsei Authors
Ahn, Sung Gwe(안성귀) ORCID logo https://orcid.org/0000-0002-8778-9686
Jeong, Joon(정준) ORCID logo https://orcid.org/0000-0003-0397-0005
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