Work

Recalibrating the apoptotic threshold: Ubiquitin‐regulated ER stress signalling in colorectal cancer

Year: 2026

Type: article

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 Ca 2+ 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 Ca 2+ 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.

Source: Clinical and Translational Discovery

DOI: 10.1002/ctd2.70217

Authors: Jing Hu, Shanliang Zheng, Ying Hu

Institutions: Harbin Institute of Technology, Ministry of Industry and Information Technology

Language: English

Topic: Endoplasmic Reticulum Stress and Disease

Subfield: Cell Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $2,420