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Hypoxic ER stress suppresses ?-catenin expression and promotes cooperation between the transcription factors XBP1 and HIF1? for cell survival.

ABSTRACT: Hypoxia occurs in many human solid tumors and activates multiple cellular adaptive-response pathways, including the unfolded protein response (UPR) in the endoplasmic reticulum (ER). Wnt/?-catenin signaling plays a critical role in tumorigenesis, and ?-catenin has been shown to enhance hypoxia-inducible factor 1? (HIF1?)-activated gene expression, thereby supporting cell survival during hypoxia. However, the molecular interplay between hypoxic ER stress, Wnt/?-catenin signaling, and HIF1?-mediated gene regulation during hypoxia remains incompletely understood. Here, we report that hypoxic ER stress reduces ?-catenin stability, which, in turn, enhances the activity of spliced X-box-binding protein 1 (XBP1s), a transcription factor and signal transducer of the UPR, in HIF1?-mediated hypoxic responses. We observed that in the RKO colon cancer cell line, which possesses a Wnt-stimulated ?-catenin signaling cascade, increased ER stress during hypoxia is accompanied by a reduction in low-density lipoprotein receptor-related protein 6 (LRP6), and this reduction in LRP6 decreased ?-catenin accumulation and impaired Wnt/?-catenin signaling. Of note, ?-catenin interacted with both XBP1s and HIF1?, suppressing XBP1s-mediated augmentation of HIF1? target gene expression. Furthermore, Wnt stimulation or ?-catenin overexpression blunted XBP1s-mediated cell survival under hypoxia. Together, these results reveal an unanticipated role for the Wnt/?-catenin pathway in hindering hypoxic UPR-mediated responses that increase cell survival. Our findings suggest that the molecular cross-talks between hypoxic ER stress, LRP6/?-catenin signaling, and the HIF1? pathway may represent an unappreciated mechanism that enables some tumor subtypes to survive and grow in hypoxic conditions.

SUBMITTER: Xia Z

PROVIDER: S-EPMC6746444 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Hypoxic ER stress suppresses β-catenin expression and promotes cooperation between the transcription factors XBP1 and HIF1α for cell survival.

Xia Zhixiong Z Wu Shiyong S Wei Xin X Liao Yifei Y Yi Ping P Liu Yong Y Liu Jianmiao J Liu Jianfeng J

The Journal of biological chemistry 20190726 37

Hypoxia occurs in many human solid tumors and activates multiple cellular adaptive-response pathways, including the unfolded protein response (UPR) in the endoplasmic reticulum (ER). Wnt/β-catenin signaling plays a critical role in tumorigenesis, and β-catenin has been shown to enhance hypoxia-inducible factor 1α (HIF1α)-activated gene expression, thereby supporting cell survival during hypoxia. However, the molecular interplay between hypoxic ER stress, Wnt/β-catenin signaling, and HIF1α-mediat ...[more]

PMID: 31350332

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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.

Dataset Information

Hypoxic ER stress suppresses ?-catenin expression and promotes cooperation between the transcription factors XBP1 and HIF1? for cell survival.

Publications

Hypoxic ER stress suppresses β-catenin expression and promotes cooperation between the transcription factors XBP1 and HIF1α for cell survival.

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