Author
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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