Hypoxic ER stress suppresses {beta}-catenin expression and promotes cooperation between the transcription factors XBP1 and HIF1{alpha} for cell survival [Signal Transduction] (Journal of Biological Chemistry)

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.