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iASPP suppression mediates terminal UPR and improves BRAF-inhibitor sensitivity of colon cancers

Abstract

Unfolded protein response (UPR) signaling is activated under endoplasmic reticulum (ER) stress, an emerging cancer hallmark, leading to either adaptive survival or cell death, while the mechanisms underlying adaptation-death switch remain poorly understood. Here, we examined whether oncogene iASPP regulates the switch and how the mechanisms can be used in colon cancer treatment. iASPP is downregulated when cells undergo transition from adaptation to death during therapy-induced ER stress. Blocking iASPP’s downregulation attenuates stress-induced cell death. Mechanistically, Hu-antigen R (HuR)-mediated stabilization of iASPP mRNA and subsequent iASPP protein production is significantly impaired with prolonged ER stress, which facilitates the degradation of GRP78, a key regulator of the UPR, in the cytosol. Because iASPP competes with GRP78 in binding the ER-resident E3 ligase RNF185, and tips the balance in favor of cell death. Positive correlation between the levels of HuR, iASPP, and GRP78 are detectable in colon cancer tissues in vivo. Genetic inhibition of iASPP/GRP78 or chemical inhibition of HuR not only inhibits tumor growth, but also sensitizes colon cancer cells’ responses to BRAF inhibitor-induced ER stress and cell death. This study provides mechanistic insights into the switch between adaptation and death during ER stress, and also identifies a potential strategy to improve BRAF-inhibitor efficiency in colon cancers.

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Fig. 1: Dynamic changes in iASPP expression define the switch.
Fig. 2: iASPP regulates the switch by stabilizing GRP78.
Fig. 3: GRP78 is a novel substrate of RNF185.
Fig. 4: iASPP competes with GRP78 to bind RNF185.
Fig. 5: HuR-mediated iASPP mRNA degradation during prolonged ER stress.
Fig. 6: HuR/iASPP is associated with GRP78 in vivo in colon cancer tissues.
Fig. 7: Chemical or genetic inhibition of HuR/iASPP-GRP78 inhibits sensitizes colon cancer cells to BRAF inhibition in vitro.
Fig. 8: Chemical or genetic inhibition of HuR/iASPP-GRP78 sensitizes colon cancer cells to BRAF inhibition in vivo.

Data availability

All data are present in the manuscript and the Supplementary Materials. Additional data related to this paper may be requested from the corresponding author.

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Funding

The work was funded by the National Key R & D Program of China (2022YFA1105200), Interdisciplinary Research Foundation of HIT, National Nature Science Foundation (Nos. 82025027, 82150115, 31871389 and 32000517), and Nature Science Foundation of Heilongjiang Province (No. YQ2021C024).

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YH designed the experiments and wrote the paper. SZ, XW, HL, DZ, and QL performed the experiments and analyzed the data. LL collected clinical samples. QJ performed the bioinformatic analysis.

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Correspondence to Li Li or Ying Hu.

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The study for human colon cancer samples has been approved by the Research Ethics Committee of Harbin Medical University, China. All animal procedures were performed according to protocols approved by the Rules for Animal Experiments published by the Chinese Government (Beijing, China) and approved by the Research Ethics Committee of Harbin Institute of Technology, China.

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Zheng, S., Wang, X., Liu, H. et al. iASPP suppression mediates terminal UPR and improves BRAF-inhibitor sensitivity of colon cancers. Cell Death Differ (2022). https://doi.org/10.1038/s41418-022-01086-w

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