Bip-Yorkie interaction determines oncogenic and tumor-suppressive roles of Ire1/Xbp1s activation
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 between the Ire1/Xbp1s and Hippo signaling pathways under physiological settings, as well as a crucial role of Bip-Yki interaction in tumorigenesis that is shared from Drosophila to humans.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:119 |
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| Enthalten in: |
Proceedings of the National Academy of Sciences of the United States of America - 119(2022), 42 vom: 18. Okt., Seite e2202133119 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Yang, Shuai [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 12.10.2022 Date Revised 11.04.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1073/pnas.2202133119 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM347307264 |
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| 100 | 1 | |a Yang, Shuai |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Bip-Yorkie interaction determines oncogenic and tumor-suppressive roles of Ire1/Xbp1s activation |
| 264 | 1 | |c 2022 | |
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| 500 | |a Date Revised 11.04.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 between the Ire1/Xbp1s and Hippo signaling pathways under physiological settings, as well as a crucial role of Bip-Yki interaction in tumorigenesis that is shared from Drosophila to humans | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Hippo signaling | |
| 650 | 4 | |a size control | |
| 650 | 4 | |a triple-negative breast cancer | |
| 650 | 4 | |a tumorigenesis | |
| 650 | 4 | |a unfolded protein response | |
| 650 | 7 | |a DNA-Binding Proteins |2 NLM | |
| 650 | 7 | |a Drosophila Proteins |2 NLM | |
| 650 | 7 | |a X-Box Binding Protein 1 |2 NLM | |
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| 700 | 1 | |a Jiang, Hua |e verfasserin |4 aut | |
| 700 | 1 | |a Bian, Weixiang |e verfasserin |4 aut | |
| 700 | 1 | |a Xu, Wenyan |e verfasserin |4 aut | |
| 700 | 1 | |a Guo, Yifan |e verfasserin |4 aut | |
| 700 | 1 | |a Song, Sha |e verfasserin |4 aut | |
| 700 | 1 | |a Zheng, Jiadong |e verfasserin |4 aut | |
| 700 | 1 | |a Kuang, Xiaoyu |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Chenxi |e verfasserin |4 aut | |
| 700 | 1 | |a Ding, Xiang |e verfasserin |4 aut | |
| 700 | 1 | |a Guo, Xiaowei |e verfasserin |4 aut | |
| 700 | 1 | |a Xue, Lei |e verfasserin |4 aut | |
| 700 | 1 | |a Yu, Zijing |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Yongdeng |e verfasserin |4 aut | |
| 700 | 1 | |a Ryoo, Hyung Don |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Xu |e verfasserin |4 aut | |
| 700 | 1 | |a Ma, Xianjue |e verfasserin |4 aut | |
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