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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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ABL1-dependent OTULIN phosphorylation promotes genotoxic Wnt/β-catenin activation to enhance drug resistance in breast cancers
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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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Journal Article
ABL1-dependent OTULIN phosphorylation promotes genotoxic Wnt/β-catenin activation to enhance drug resistance in breast cancers
2020
Overview
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.
Genotoxic agents have been shown to activate the Wnt/β-catenin signaling but the underlying mechanism remains unclear. Here, the authors show that upon DNA damage, the deubiquitinase OTULIN activates Wnt/β-catenin signaling by inhibiting linear ubiquitination, K48-linked polyubiquitination, and proteasomal degradation of β-catenin.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/109
/ 13/2
/ 13/89
/ 13/95
/ 14/5
/ 631/337
/ 631/67
/ 64/60
/ 96/63
/ Animals
/ Breast Neoplasms - metabolism
/ Breast Neoplasms - pathology
/ Damage
/ DNA
/ Female
/ Humanities and Social Sciences
/ Humans
/ Phosphotyrosine - metabolism
/ Proto-Oncogene Proteins c-abl - metabolism
/ Science
/ Tumors
