S100A11 sustains STRAP stability to drive PI3K/AKT/NF-κB feedforward signalling circuit activation in colorectal cancer progression

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.