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

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.

SUBMITTER: Wang W

PROVIDER: S-EPMC7414915 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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

Wang Wei W Li Mingqi M Ponnusamy Suriyan S Chi Yayun Y Xue Jingyan J Fahmy Beshoy B Fan Meiyun M Miranda-Carboni Gustavo A GA Narayanan Ramesh R Wu Jiong J Wu Zhao-Hui ZH

Nature communications 20200807 1

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 f ...[more]

PMID: 32770022

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Project description:Triggering Receptor Expressed on Myeloid cells 2 (TREM2), which is expressed on myeloid cells including microglia in the CNS, has recently been identified as a risk factor for Alzheimer's disease (AD). TREM2 transmits intracellular signals through its transmembrane binding partner DNAX-activating protein 12 (DAP12). Homozygous mutations inactivating TREM2 or DAP12 lead to Nasu-Hakola disease; however, how AD risk-conferring variants increase AD risk is not clear. To elucidate the signaling pathways underlying reduced TREM2 expression or loss of function in microglia, we respectively knocked down and knocked out the expression of TREM2 in in vitro and in vivo models. We found that TREM2 deficiency reduced the viability and proliferation of primary microglia, reduced microgliosis in Trem2-/- mouse brains, induced cell cycle arrest at the G1/S checkpoint, and decreased the stability of β-catenin, a key component of the canonical Wnt signaling pathway responsible for maintaining many biological processes, including cell survival. TREM2 stabilized β-catenin by inhibiting its degradation via the Akt/GSK3β signaling pathway. More importantly, treatment with Wnt3a, LiCl, or TDZD-8, which activates the β-catenin-mediated Wnt signaling pathway, rescued microglia survival and microgliosis in Trem2-/- microglia and/or in Trem2-/- mouse brain. Together, our studies demonstrate a critical role of TREM2-mediated Wnt/β-catenin pathway in microglial viability and suggest that modulating this pathway therapeutically may help to combat the impaired microglial survival and microgliosis associated with AD.SIGNIFICANCE STATEMENT Mutations in the TREM2 (Triggering Receptor Expressed on Myeloid cells 2) gene are associated with increased risk for Alzheimer's disease (AD) with effective sizes comparable to that of the apolipoprotein E (APOE) ε4 allele, making it imperative to understand the molecular pathway(s) underlying TREM2 function in microglia. Our findings shed new light on the relationship between TREM2/DNAX-activating protein 12 (DAP12) signaling and Wnt/β-catenin signaling and provide clues as to how reduced TREM2 function might impair microglial survival in AD pathogenesis. We demonstrate that TREM2 promotes microglial survival by activating the Wnt/β-catenin signaling pathway and that it is possible to restore Wnt/β-catenin signaling when TREM2 activity is disrupted or reduced. Therefore, we demonstrate the potential for manipulating the TREM2/β-catenin signaling pathway for the treatment of AD.

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Dataset Information

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

Publications

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

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