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Tumor suppressor mediated ubiquitylation of hnRNPK is a barrier to oncogenic translation

Author

Listed:
  • Bartosz Mucha

    (Case Comprehensive Cancer Center, Case Western Reserve University)

  • Shuo Qie

    (Case Comprehensive Cancer Center, Case Western Reserve University)

  • Sagar Bajpai

    (Case Comprehensive Cancer Center, Case Western Reserve University)

  • Vincenzo Tarallo

    (Case Comprehensive Cancer Center, Case Western Reserve University)

  • J. Nathaniel Diehl

    (University of North Carolina at Chapel Hill)

  • Frank Tedeschi

    (Case Comprehensive Cancer Center, Case Western Reserve University
    Case Comprehensive Cancer Center, Case Western Reserve University)

  • Gao Zhou

    (Case Comprehensive Cancer Center, Case Western Reserve University)

  • Zhaofeng Gao

    (Case Western Reserve University)

  • Samuel Flashner

    (Columbia University Irving Medical Center)

  • Andres J. Klein-Szanto

    (Fox Chase Cancer Center)

  • Hanina Hibshoosh

    (Columbia University Irving Medical Center)

  • Shimonosono Masataka

    (Columbia University Irving Medical Center)

  • Olga S. Chajewski

    (Medical University of South Carolina)

  • Ireneusz Majsterek

    (Medical University of Lodz)

  • Dariusz Pytel

    (Medical University of South Carolina
    Medical University of Lodz)

  • Maria Hatzoglou

    (Case Western Reserve University)

  • Channing J. Der

    (University of North Carolina at Chapel Hill
    University of North Carolina at Chapel Hill
    University of North Carolina at Chapel Hill)

  • Hiroshi Nakagawa

    (Columbia University Irving Medical Center)

  • Adam J. Bass

    (Columbia University Irving Medical Center)

  • Kwok-Kin Wong

    (New York University)

  • Serge Y. Fuchs

    (University of Pennsylvania)

  • Anil K. Rustgi

    (Columbia University Irving Medical Center)

  • Eckhard Jankowsky

    (Case Comprehensive Cancer Center, Case Western Reserve University
    Case Comprehensive Cancer Center, Case Western Reserve University
    Case Comprehensive Cancer Center, Case Western Reserve University)

  • J. Alan Diehl

    (Case Comprehensive Cancer Center, Case Western Reserve University
    Case Comprehensive Cancer Center, Case Western Reserve University
    Case Comprehensive Cancer Center, Case Western Reserve University)

Abstract

Heterogeneous Nuclear Ribonucleoprotein K (hnRNPK) is a multifunctional RNA binding protein (RBP) localized in the nucleus and the cytoplasm. Abnormal cytoplasmic enrichment observed in solid tumors often correlates with poor clinical outcome. The mechanism of cytoplasmic redistribution and ensuing functional role of cytoplasmic hnRNPK remain unclear. Here we demonstrate that the SCFFbxo4 E3 ubiquitin ligase restricts the pro-oncogenic activity of hnRNPK via K63 linked polyubiquitylation, thus limiting its ability to bind target mRNA. We identify SCFFbxo4-hnRNPK responsive mRNAs whose products regulate cellular processes including proliferation, migration, and invasion. Loss of SCFFbxo4 leads to enhanced cell invasion, migration, and tumor metastasis. C-Myc was identified as one target of SCFFbxo4-hnRNPK. Fbxo4 loss triggers hnRNPK-dependent increase in c-Myc translation, thereby contributing to tumorigenesis. Increased c-Myc positions SCFFbxo4-hnRNPK dysregulated cancers for potential therapeutic interventions that target c-Myc-dependence. This work demonstrates an essential role for limiting cytoplasmic hnRNPK function in order to maintain translational and cellular homeostasis.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34402-6
    DOI: 10.1038/s41467-022-34402-6
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    1. Mitsuteru Natsuizaka & Kelly A. Whelan & Shingo Kagawa & Koji Tanaka & Veronique Giroux & Prasanna M. Chandramouleeswaran & Apple Long & Varun Sahu & Douglas S. Darling & Jianwen Que & Yizeng Yang & J, 2017. "Interplay between Notch1 and Notch3 promotes EMT and tumor initiation in squamous cell carcinoma," Nature Communications, Nature, vol. 8(1), pages 1-16, December.
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    3. 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.
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