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

Wei Wang, Mingqi Li, Suriyan Ponnusamy, Yayun Chi, Jingyan Xue, Beshoy Fahmy, Meiyun Fan, Gustavo A. Miranda-Carboni, Ramesh Narayanan, Jiong Wu and Zhao-Hui Wu ()
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Wei Wang: University of Tennessee Health Science Center
Mingqi Li: University of Tennessee Health Science Center
Suriyan Ponnusamy: University of Tennessee Health Science Center
Yayun Chi: Fudan University Shanghai Cancer Center
Jingyan Xue: Fudan University Shanghai Cancer Center
Beshoy Fahmy: University of Tennessee Health Science Center
Meiyun Fan: University of Tennessee Health Science Center
Gustavo A. Miranda-Carboni: University of Tennessee Health Science Center
Ramesh Narayanan: University of Tennessee Health Science Center
Jiong Wu: Fudan University Shanghai Cancer Center
Zhao-Hui Wu: University of Tennessee Health Science Center

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-17770-9

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