Recalibrating the apoptotic threshold: Ubiquitin‐regulated ER stress signalling in colorectal cancer
- 1Key Laboratory of Science and Technology and Intelligent Equipment for the Prevention and Control of Major Chronic Diseases Ministry of Industry and Information Technology, Zhengzhou Advanced Research Institute, Harbin Institute of Technology Zhengzhou China
- 2School of Life Science and Technology Harbin Institute of Technology Harbin China
Abstract
Background Colorectal cancer (CRC) cells survive persistent proteotoxic stress imposed by the tumour microenvironment. Although the unfolded protein response (UPR) is widely recognised as an adaptive signalling network, how its amplitude and duration are coupled to apoptotic‐threshold control—and thereby to cell‐fate decisions—remains incompletely understood. Review findings This review synthesises evidence that ubiquitin‐dependent regulation, mediated through the ubiquitin–proteasome system (UPS) and ER‐associated degradation (ERAD), forms a post‐translational signalling layer that recalibrates apoptotic competence during chronic ER stress. By controlling the abundance, activity, and turnover of UPR sensors, ER chaperones, regulators of ER Ca2+ homeostasis, and short‐lived apoptotic proteins, this layer can influence whether CRC cells sustain adaptive signalling or progress towards terminal stress responses. We distinguish extensively validated apoptosis‐regulatory pathways, including FBXW7–MCL‐1 and MDM2–p53, from mechanistically supported but CRC‐context‐limited regulation such as SYVN1‐mediated IRE1α turnover and from emerging or hypothesis‐generating mechanisms, including USP14‐associated IRE1α regulation, RNF39–RINT1, HuR–iASPP–RNF185–GRP78, and iASPP–Gp78–TMCO1. Within this evidence‐weighted framework, we use rheostatic sensor tuning and the proposed concept of competitive E3 shielding as organising models for understanding how ubiquitin‐dependent processes may shape proteostasis capacity, UPR output, ER Ca2+ homeostasis, and mitochondrial apoptotic competence. We further discuss how hypoxia, nutrient limitation, microbiota‐derived metabolites, and therapy‐induced stress remodel these ubiquitin programs. Finally, we critically evaluate translational opportunities and limitations associated with targeted protein degradation, conceptual proteostasis‐state biomarker frameworks, and synthetic‐lethal strategies that combine stress induction with blockade of adaptive proteostasis. Conclusions We propose that ubiquitin‐regulated ER‐stress signalling functions as a context‐dependent cell‐fate rheostat in CRC. Selective disruption of validated or tumour‐dependent proteostasis nodes, rather than broad proteasome inhibition, may restore apoptotic competence in defined CRC contexts. Whether such interventions can reproducibly promote bona fide immunogenic cell death or improve responsiveness to immunotherapy remains context dependent and requires direct functional and clinical validation.
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BibTeX
@article{hu2026recalibrating,
title = {{Recalibrating the apoptotic threshold: Ubiquitin‐regulated ER stress signalling in colorectal cancer}},
author = {Jing Hu and Shanliang Zheng and Ying Hu},
journal = {Clinical and Translational Discovery},
year = {2026},
month = oct,
doi = {10.1002/ctd2.70217},
url = {https://doi.org/10.1002/ctd2.70217},
note = {CC BY},
}
RIS
TY - JOUR
TI - Recalibrating the apoptotic threshold: Ubiquitin‐regulated ER stress signalling in colorectal cancer
AU - Jing Hu
AU - Shanliang Zheng
AU - Ying Hu
PY - 2026
DA - 2026/10/26
JO - Clinical and Translational Discovery
DO - 10.1002/ctd2.70217
UR - https://doi.org/10.1002/ctd2.70217
AB - Background Colorectal cancer (CRC) cells survive persistent proteotoxic stress imposed by the tumour microenvironment. Although the unfolded protein response (UPR) is widely recognised as an adaptive signalling network, how its amplitude and duration are coupled to apoptotic‐threshold control—and thereby to cell‐fate decisions—remains incompletely understood. Review findings This review synthesises evidence that ubiquitin‐dependent regulation, mediated through the ubiquitin–proteasome system (UPS) and ER‐associated degradation (ERAD), forms a post‐translational signalling layer that recalibrates apoptotic competence during chronic ER stress. By controlling the abundance, activity, and turnover of UPR sensors, ER chaperones, regulators of ER Ca2+ homeostasis, and short‐lived apoptotic proteins, this layer can influence whether CRC cells sustain adaptive signalling or progress towards terminal stress responses. We distinguish extensively validated apoptosis‐regulatory pathways, including FBXW7–MCL‐1 and MDM2–p53, from mechanistically supported but CRC‐context‐limited regulation such as SYVN1‐mediated IRE1α turnover and from emerging or hypothesis‐generating mechanisms, including USP14‐associated IRE1α regulation, RNF39–RINT1, HuR–iASPP–RNF185–GRP78, and iASPP–Gp78–TMCO1. Within this evidence‐weighted framework, we use rheostatic sensor tuning and the proposed concept of competitive E3 shielding as organising models for understanding how ubiquitin‐dependent processes may shape proteostasis capacity, UPR output, ER Ca2+ homeostasis, and mitochondrial apoptotic competence. We further discuss how hypoxia, nutrient limitation, microbiota‐derived metabolites, and therapy‐induced stress remodel these ubiquitin programs. Finally, we critically evaluate translational opportunities and limitations associated with targeted protein degradation, conceptual proteostasis‐state biomarker frameworks, and synthetic‐lethal strategies that combine stress induction with blockade of adaptive proteostasis. Conclusions We propose that ubiquitin‐regulated ER‐stress signalling functions as a context‐dependent cell‐fate rheostat in CRC. Selective disruption of validated or tumour‐dependent proteostasis nodes, rather than broad proteasome inhibition, may restore apoptotic competence in defined CRC contexts. Whether such interventions can reproducibly promote bona fide immunogenic cell death or improve responsiveness to immunotherapy remains context dependent and requires direct functional and clinical validation.
SN - 2768-0622
ER -