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- Open access
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- Han Yang2,3 na1,
- Ziyuan Xu1 na1,
- Hao Dong1,
- Zhaojun Kou1,
- Linlin Lu4 &
- …
- Xuezhen Ma ORCID: orcid.org/0009-0001-9368-51381
Cell Death & Disease (2026) Cite this article
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Abstract
Colorectal cancer (CRC) remains one of the most prevalent malignancies worldwide, with persistently low rates of early-stage diagnosis, poor overall prognosis, and a propensity for therapeutic resistance—challenges that underscore the urgent need for deeper mechanistic insight. By integrating single-cell transcriptomic data (GSE161277) with multi-omics datasets from TCGA and GEO repositories, alongside an independent clinical cohort, we identified S100A11 as a consistently overexpressed gene in CRC that correlates significantly with adverse patient outcomes. Functional studies established that S100A11 drives tumour progression by promoting cell proliferation, suppressing apoptosis, and inducing epithelial-to-mesenchymal transition (EMT). Mechanistically, S100A11 engages the WD6-7 domain (residues 221–302) of STRAP through direct physical interaction, thereby recruiting the deubiquitylase OTUB1 to shield lysine K246 of STRAP from K63-linked polyubiquitination. This protection stabilises STRAP and facilitates its association with PI3K, culminating in activation of the PI3K/AKT/NF-κB cascade and nuclear translocation of p65. We further demonstrate that p65 binds directly to the promoter regions of both S100A11 and STRAP, transcriptionally upregulating their expression and establishing a self-reinforcing feedforward loop that sustains pathway activation. Collectively, these findings delineate a hierarchical regulatory network centred on the S100A11/STRAP/NF-κB axis and offer a mechanistic framework with potential implications for CRC diagnosis and targeted intervention.
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This research was supported by the National Natural Science Foundation of China (No.32471518).
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The authors declare no competing interests.
Ethics
All experimental procedures involving animals and human tissue samples were conducted in accordance with relevant institutional guidelines and regulatory requirements. Animal experiments were reviewed and approved by the Ethics Committee of Qingdao Central Hospital (Ethics No. 2024-1087). Human tissue microarray samples were obtained with informed patient consent and approved by the Biomedical Ethics Review Committee of Shanghai Outdo Biotech Co., Ltd. (Approval Nos.: SHYJS-CP-230903; SHYJS-CP-1704001).
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Li, J., Yang, H., Xu, Z. et al. S100A11 sustains STRAP stability to drive PI3K/AKT/NF-κB feedforward signalling circuit activation in colorectal cancer progression. Cell Death Dis (2026). https://doi.org/10.1038/s41419-026-09117-x
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DOI: https://doi.org/10.1038/s41419-026-09117-x