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.
Highlights
Dysregulated Wnt/β-catenin activation plays a critical role in cancer progression, metastasis, and drug resistance
Β-catenin levels were substantially increased in MDA-MB-231 cells treated by various genotoxic drugs, including Dox, carboplatin (CBP) and irinotecan (CPT-11), which was accompanied by increased Wnt/β-catenin transactivity measured by TOPFlash reporter assay (Fig. 1a) and upregulated transcription of a canonical Wnt target gene AXIN2 (Supplementary Fig. 1B)
We demonstrated that β-catenin is attached with M1-linked polyubiquitin catalyzed by the LUBAC ligase complex, which enhances βcatenin degradation
Summary
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 the underlying mechanism remains incompletely understood. We show that genotoxic agent-activated Wnt/β-catenin signaling is independent of the FZD/LRP heterodimeric receptors and Wnt ligands. The association with β-catenin is enhanced by OTULIN Tyr[56] 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. OTULIN-mediated Wnt/β-catenin activation upon genotoxic treatments promotes drug resistance and metastasis in breast cancers. The signaling output of the canonical Wnt pathway is determined by the level of cytosolic β-catenin, which is under the strict control of the destruction complex. The destruction complex is composed of AXIN, APC
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