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

Autor:	Wang W; Department of Radiation Oncology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN, 38103, USA.; Department of Pathology and Laboratory Medicine, College of Medicine, University of Tennessee Health Science Center, Memphis, TN, 38103, USA.; Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, 38103, USA., Li M; Department of Pathology and Laboratory Medicine, College of Medicine, University of Tennessee Health Science Center, Memphis, TN, 38103, USA.; Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, 38103, USA., Ponnusamy S; Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, 38103, USA.; Department of Medicine, College of Medicine, University of Tennessee Health Science Center, Memphis, TN, 38103, USA., Chi Y; Department of Oncology, Fudan University Shanghai Cancer Center, Shanghai, PR China.; Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, PR China., Xue J; Department of Oncology, Fudan University Shanghai Cancer Center, Shanghai, PR China.; Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, PR China., Fahmy B; Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, 38103, USA., Fan M; Department of Pathology and Laboratory Medicine, College of Medicine, University of Tennessee Health Science Center, Memphis, TN, 38103, USA.; Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, 38103, USA., Miranda-Carboni GA; Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, 38103, USA.; Department of Medicine, College of Medicine, University of Tennessee Health Science Center, Memphis, TN, 38103, USA., Narayanan R; Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, 38103, USA.; Department of Medicine, College of Medicine, University of Tennessee Health Science Center, Memphis, TN, 38103, USA., Wu J; Department of Oncology, Fudan University Shanghai Cancer Center, Shanghai, PR China.; Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, PR China., Wu ZH; Department of Radiation Oncology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN, 38103, USA. zwu6@uthsc.edu.; Department of Pathology and Laboratory Medicine, College of Medicine, University of Tennessee Health Science Center, Memphis, TN, 38103, USA. zwu6@uthsc.edu.; Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, 38103, USA. zwu6@uthsc.edu.
Jazyk:	angličtina
Zdroj:	Nature communications [Nat Commun] 2020 Aug 07; Vol. 11 (1), pp. 3965. Date of Electronic Publication: 2020 Aug 07.
DOI:	10.1038/s41467-020-17770-9
Abstrakt:	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.
Databáze:	MEDLINE
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