Bip-Yorkie interaction determines oncogenic and tumor-suppressive roles of Ire1/Xbp1s activation

作者：Shuai Yang, Hua Jiang, Weixiang Bian, Wenyan Xu, Yifan Guo, Sha Song, Jiadong Zheng, Xiaoyu Kuang, Chenxi Wu, Xiang Ding, Xiaowei Guo, Lei Xue, Zijing Yu, Yongdeng Zhang, Hyung Don Ryoo, Xu Li, Xianjue Ma · 发表于：Proceedings of the National Academy of Sciences · 年份：2022 · DOI：10.1073/pnas.2202133119 · 被引用次数：24 · 研究领域：Hippo pathway signaling and YAP/TAZ、Microtubule and mitosis dynamics、Ubiquitin and proteasome pathways

Unfolded protein response (UPR) is the mechanism by which cells control endoplasmic reticulum (ER) protein homeostasis. ER proteostasis is essential to adapt to cell proliferation and regeneration in development and tumorigenesis, but mechanisms linking UPR, growth control, and cancer progression remain unclear. Here, we report that the Ire1/Xbp1s pathway has surprisingly oncogenic and tumor-suppressive roles in a context-dependent manner. Activation of Ire1/Xbp1s up-regulates their downstream target Bip, which sequesters Yorkie (Yki), a Hippo pathway transducer, in the cytoplasm to restrict Yki transcriptional output. This regulation provides an endogenous defensive mechanism in organ size control, intestinal homeostasis, and regeneration. Unexpectedly, Xbp1 ablation promotes tumor overgrowth but suppresses invasiveness in a Drosophila cancer model. Mechanistically, hyperactivated Ire1/Xbp1s signaling in turn induces JNK-dependent developmental and oncogenic cell migration and epithelial-mesenchymal transition (EMT) via repression of Yki. In humans, a negative correlation between XBP1 and YAP (Yki ortholog) target gene expression specifically exists in triple-negative breast cancers (TNBCs), and those with high XBP1 or HSPA5 (Bip ortholog) expression have better clinical outcomes. In human TNBC cell lines and xenograft models, ectopic XBP1s or HSPA5 expression alleviates tumor growth but aggravates cell migration and invasion. These findings uncover a conserved crosstalk bet...