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Fbxo4-mediated degradation of Fxr1 suppresses tumorigenesis in head and neck squamous cell carcinoma

Author

Listed:
  • Shuo Qie

    (Medical University of South Carolina)

  • Mrinmoyee Majumder

    (Medical University of South Carolina
    Medical University of South Carolina)

  • Katarzyna Mackiewicz

    (Medical University of South Carolina)

  • Breege V. Howley

    (Medical University of South Carolina)

  • Yuri K. Peterson

    (Medical University of South Carolina)

  • Philip H. Howe

    (Medical University of South Carolina)

  • Viswanathan Palanisamy

    (Medical University of South Carolina
    Medical University of South Carolina)

  • J. Alan Diehl

    (Medical University of South Carolina)

Abstract

The Fbxo4 tumour suppressor is a component of an Skp1-Cul1-F-box E3 ligase for which two substrates are known. Here we show purification of SCFFbxo4 complexes results in the identification of fragile X protein family (FMRP, Fxr1 and Fxr2) as binding partners. Biochemical and functional analyses reveal that Fxr1 is a direct substrate of SCFFbxo4. Consistent with a substrate relationship, Fxr1 is overexpressed in Fbxo4 knockout cells, tissues and in human cancer cells, harbouring inactivating Fbxo4 mutations. Critically, in head and neck squamous cell carcinoma, Fxr1 overexpression correlates with reduced Fbxo4 levels in the absence of mutations or loss of mRNA, suggesting the potential for feedback regulation. Direct analysis reveals that Fbxo4 translation is attenuated by Fxr1, indicating the existence of a feedback loop that contributes to Fxr1 overexpression and the loss of Fbxo4. Ultimately, the consequence of Fxr1 overexpression is the bypass of senescence and neoplastic progression.

Suggested Citation

  • Shuo Qie & Mrinmoyee Majumder & Katarzyna Mackiewicz & Breege V. Howley & Yuri K. Peterson & Philip H. Howe & Viswanathan Palanisamy & J. Alan Diehl, 2017. "Fbxo4-mediated degradation of Fxr1 suppresses tumorigenesis in head and neck squamous cell carcinoma," Nature Communications, Nature, vol. 8(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-01199-8
    DOI: 10.1038/s41467-017-01199-8
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    Cited by:

    1. Ram Bhupal Reddy & Samanta S Khora & Amritha Suresh, 2019. "Molecular prognosticators in clinically and pathologically distinct cohorts of head and neck squamous cell carcinoma—A meta-analysis approach," PLOS ONE, Public Library of Science, vol. 14(7), pages 1-29, July.
    2. Bartosz Mucha & Shuo Qie & Sagar Bajpai & Vincenzo Tarallo & J. Nathaniel Diehl & Frank Tedeschi & Gao Zhou & Zhaofeng Gao & Samuel Flashner & Andres J. Klein-Szanto & Hanina Hibshoosh & Shimonosono M, 2022. "Tumor suppressor mediated ubiquitylation of hnRNPK is a barrier to oncogenic translation," Nature Communications, Nature, vol. 13(1), pages 1-18, December.

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