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ABL1-dependent OTULIN phosphorylation promotes genotoxic Wnt/β-catenin activation to enhance drug resistance in breast cancers

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Listed:
  • Wei Wang

    (University of Tennessee Health Science Center
    University of Tennessee Health Science Center
    University of Tennessee Health Science Center)

  • Mingqi Li

    (University of Tennessee Health Science Center
    University of Tennessee Health Science Center)

  • Suriyan Ponnusamy

    (University of Tennessee Health Science Center
    University of Tennessee Health Science Center)

  • Yayun Chi

    (Fudan University Shanghai Cancer Center
    Fudan University Shanghai Cancer Center)

  • Jingyan Xue

    (Fudan University Shanghai Cancer Center
    Fudan University Shanghai Cancer Center)

  • Beshoy Fahmy

    (University of Tennessee Health Science Center)

  • Meiyun Fan

    (University of Tennessee Health Science Center
    University of Tennessee Health Science Center)

  • Gustavo A. Miranda-Carboni

    (University of Tennessee Health Science Center
    University of Tennessee Health Science Center)

  • Ramesh Narayanan

    (University of Tennessee Health Science Center
    University of Tennessee Health Science Center)

  • Jiong Wu

    (Fudan University Shanghai Cancer Center
    Fudan University Shanghai Cancer Center)

  • Zhao-Hui Wu

    (University of Tennessee Health Science Center
    University of Tennessee Health Science Center
    University of Tennessee Health Science Center)

Abstract

Dysregulated Wnt/β-catenin activation plays a critical role in cancer progression, metastasis, and drug resistance. Genotoxic agents such as radiation and chemotherapeutics have been shown to activate the Wnt/β-catenin signaling although the underlying mechanism remains incompletely understood. Here, we show that genotoxic agent-activated Wnt/β-catenin signaling is independent of the FZD/LRP heterodimeric receptors and Wnt ligands. OTULIN, a linear linkage-specific deubiquitinase, is essential for the DNA damage-induced β-catenin activation. OTULIN inhibits linear ubiquitination of β-catenin, which attenuates its Lys48-linked ubiquitination and proteasomal degradation upon DNA damage. The association with β-catenin is enhanced by OTULIN Tyr56 phosphorylation, which depends on genotoxic stress-activated ABL1/c-Abl. Inhibiting OTULIN or Wnt/β-catenin sensitizes triple-negative breast cancer xenograft tumors to chemotherapeutics and reduces metastasis. Increased OTULIN levels are associated with aggressive molecular subtypes and poor survival in breast cancer patients. Thus, OTULIN-mediated Wnt/β-catenin activation upon genotoxic treatments promotes drug resistance and metastasis in breast cancers.

Suggested Citation

  • Wei Wang & Mingqi Li & Suriyan Ponnusamy & Yayun Chi & Jingyan Xue & Beshoy Fahmy & Meiyun Fan & Gustavo A. Miranda-Carboni & Ramesh Narayanan & Jiong Wu & Zhao-Hui Wu, 2020. "ABL1-dependent OTULIN phosphorylation promotes genotoxic Wnt/β-catenin activation to enhance drug resistance in breast cancers," Nature Communications, Nature, vol. 11(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-17770-9
    DOI: 10.1038/s41467-020-17770-9
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