FBXO11 promotes ubiquitination of the Snail family of transcription factors in cancer progression and epidermal development

Yue Jin, Anitha K. Shenoy, Samuel Doernberg, Hao Chen, Huacheng Luo, Huangxuan Shen, Tong Lin, Miriam Tarrash, Qingsong Cai, Xin Hu, Ryan Fiske, Ting Chen, Lizi Wu, Kamal A. Mohammed, Veerle Rottiers, Siu Sylvia Lee, Jianrong Lu

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

The Snail family of transcription factors are core inducers of epithelial-to-mesenchymal transition (EMT). Here we show that the F-box protein FBXO11 recognizes and promotes ubiquitin-mediated degradation of multiple Snail family members including Scratch. The association between FBXO11 and Snai1 in vitro is independent of Snai1 phosphorylation. Overexpression of FBXO11 in mesenchymal cells reduces Snail protein abundance and cellular invasiveness. Conversely, depletion of endogenous FBXO11 in epithelial cancer cells causes Snail protein accumulation, EMT, and tumor invasion, as well as loss of estrogen receptor expression in breast cancer cells. Expression of FBXO11 is downregulated by EMT-inducing signals TGFβ and nickel. In human cancer, high FBXO11 levels correlate with expression of epithelial markers and favorable prognosis. The results suggest that FBXO11 sustains the epithelial state and inhibits cancer progression. Inactivation of FBXO11 in mice leads to neonatal lethality, epidermal thickening, and increased Snail protein levels in epidermis, validating that FBXO11 is a physiological ubiquitin ligase of Snail. Moreover, in C. elegans, the FBXO11 mutant phenotype is attributed to the Snail factors as it is suppressed by inactivation/depletion of Snail homologs. Collectively, these findings suggest that the FBXO11-Snail regulatory axis is evolutionarily conserved and critically governs carcinoma progression and mammalian epidermal development.

Original languageEnglish (US)
Pages (from-to)70-82
Number of pages13
JournalCancer Letters
Volume362
Issue number1
DOIs
StatePublished - Jan 1 2015

Fingerprint

Ubiquitination
Snails
Epithelial-Mesenchymal Transition
Neoplasms
Ubiquitin
F-Box Proteins
Proteins
Ligases
Nickel
Epidermis
Estrogen Receptors
Snail Family Transcription Factors
Down-Regulation
Epithelial Cells
Phosphorylation
Breast Neoplasms
Carcinoma
Phenotype

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Jin, Yue ; Shenoy, Anitha K. ; Doernberg, Samuel ; Chen, Hao ; Luo, Huacheng ; Shen, Huangxuan ; Lin, Tong ; Tarrash, Miriam ; Cai, Qingsong ; Hu, Xin ; Fiske, Ryan ; Chen, Ting ; Wu, Lizi ; Mohammed, Kamal A. ; Rottiers, Veerle ; Lee, Siu Sylvia ; Lu, Jianrong. / FBXO11 promotes ubiquitination of the Snail family of transcription factors in cancer progression and epidermal development. In: Cancer Letters. 2015 ; Vol. 362, No. 1. pp. 70-82.
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abstract = "The Snail family of transcription factors are core inducers of epithelial-to-mesenchymal transition (EMT). Here we show that the F-box protein FBXO11 recognizes and promotes ubiquitin-mediated degradation of multiple Snail family members including Scratch. The association between FBXO11 and Snai1 in vitro is independent of Snai1 phosphorylation. Overexpression of FBXO11 in mesenchymal cells reduces Snail protein abundance and cellular invasiveness. Conversely, depletion of endogenous FBXO11 in epithelial cancer cells causes Snail protein accumulation, EMT, and tumor invasion, as well as loss of estrogen receptor expression in breast cancer cells. Expression of FBXO11 is downregulated by EMT-inducing signals TGFβ and nickel. In human cancer, high FBXO11 levels correlate with expression of epithelial markers and favorable prognosis. The results suggest that FBXO11 sustains the epithelial state and inhibits cancer progression. Inactivation of FBXO11 in mice leads to neonatal lethality, epidermal thickening, and increased Snail protein levels in epidermis, validating that FBXO11 is a physiological ubiquitin ligase of Snail. Moreover, in C. elegans, the FBXO11 mutant phenotype is attributed to the Snail factors as it is suppressed by inactivation/depletion of Snail homologs. Collectively, these findings suggest that the FBXO11-Snail regulatory axis is evolutionarily conserved and critically governs carcinoma progression and mammalian epidermal development.",
author = "Yue Jin and Shenoy, {Anitha K.} and Samuel Doernberg and Hao Chen and Huacheng Luo and Huangxuan Shen and Tong Lin and Miriam Tarrash and Qingsong Cai and Xin Hu and Ryan Fiske and Ting Chen and Lizi Wu and Mohammed, {Kamal A.} and Veerle Rottiers and Lee, {Siu Sylvia} and Jianrong Lu",
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Jin, Y, Shenoy, AK, Doernberg, S, Chen, H, Luo, H, Shen, H, Lin, T, Tarrash, M, Cai, Q, Hu, X, Fiske, R, Chen, T, Wu, L, Mohammed, KA, Rottiers, V, Lee, SS & Lu, J 2015, 'FBXO11 promotes ubiquitination of the Snail family of transcription factors in cancer progression and epidermal development', Cancer Letters, vol. 362, no. 1, pp. 70-82. https://doi.org/10.1016/j.canlet.2015.03.037

FBXO11 promotes ubiquitination of the Snail family of transcription factors in cancer progression and epidermal development. / Jin, Yue; Shenoy, Anitha K.; Doernberg, Samuel; Chen, Hao; Luo, Huacheng; Shen, Huangxuan; Lin, Tong; Tarrash, Miriam; Cai, Qingsong; Hu, Xin; Fiske, Ryan; Chen, Ting; Wu, Lizi; Mohammed, Kamal A.; Rottiers, Veerle; Lee, Siu Sylvia; Lu, Jianrong.

In: Cancer Letters, Vol. 362, No. 1, 01.01.2015, p. 70-82.

Research output: Contribution to journalArticle

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T1 - FBXO11 promotes ubiquitination of the Snail family of transcription factors in cancer progression and epidermal development

AU - Jin, Yue

AU - Shenoy, Anitha K.

AU - Doernberg, Samuel

AU - Chen, Hao

AU - Luo, Huacheng

AU - Shen, Huangxuan

AU - Lin, Tong

AU - Tarrash, Miriam

AU - Cai, Qingsong

AU - Hu, Xin

AU - Fiske, Ryan

AU - Chen, Ting

AU - Wu, Lizi

AU - Mohammed, Kamal A.

AU - Rottiers, Veerle

AU - Lee, Siu Sylvia

AU - Lu, Jianrong

PY - 2015/1/1

Y1 - 2015/1/1

N2 - The Snail family of transcription factors are core inducers of epithelial-to-mesenchymal transition (EMT). Here we show that the F-box protein FBXO11 recognizes and promotes ubiquitin-mediated degradation of multiple Snail family members including Scratch. The association between FBXO11 and Snai1 in vitro is independent of Snai1 phosphorylation. Overexpression of FBXO11 in mesenchymal cells reduces Snail protein abundance and cellular invasiveness. Conversely, depletion of endogenous FBXO11 in epithelial cancer cells causes Snail protein accumulation, EMT, and tumor invasion, as well as loss of estrogen receptor expression in breast cancer cells. Expression of FBXO11 is downregulated by EMT-inducing signals TGFβ and nickel. In human cancer, high FBXO11 levels correlate with expression of epithelial markers and favorable prognosis. The results suggest that FBXO11 sustains the epithelial state and inhibits cancer progression. Inactivation of FBXO11 in mice leads to neonatal lethality, epidermal thickening, and increased Snail protein levels in epidermis, validating that FBXO11 is a physiological ubiquitin ligase of Snail. Moreover, in C. elegans, the FBXO11 mutant phenotype is attributed to the Snail factors as it is suppressed by inactivation/depletion of Snail homologs. Collectively, these findings suggest that the FBXO11-Snail regulatory axis is evolutionarily conserved and critically governs carcinoma progression and mammalian epidermal development.

AB - The Snail family of transcription factors are core inducers of epithelial-to-mesenchymal transition (EMT). Here we show that the F-box protein FBXO11 recognizes and promotes ubiquitin-mediated degradation of multiple Snail family members including Scratch. The association between FBXO11 and Snai1 in vitro is independent of Snai1 phosphorylation. Overexpression of FBXO11 in mesenchymal cells reduces Snail protein abundance and cellular invasiveness. Conversely, depletion of endogenous FBXO11 in epithelial cancer cells causes Snail protein accumulation, EMT, and tumor invasion, as well as loss of estrogen receptor expression in breast cancer cells. Expression of FBXO11 is downregulated by EMT-inducing signals TGFβ and nickel. In human cancer, high FBXO11 levels correlate with expression of epithelial markers and favorable prognosis. The results suggest that FBXO11 sustains the epithelial state and inhibits cancer progression. Inactivation of FBXO11 in mice leads to neonatal lethality, epidermal thickening, and increased Snail protein levels in epidermis, validating that FBXO11 is a physiological ubiquitin ligase of Snail. Moreover, in C. elegans, the FBXO11 mutant phenotype is attributed to the Snail factors as it is suppressed by inactivation/depletion of Snail homologs. Collectively, these findings suggest that the FBXO11-Snail regulatory axis is evolutionarily conserved and critically governs carcinoma progression and mammalian epidermal development.

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