PIAS1 circRNA-translated novel protein inhibits NF-κB signaling pathway by promoting the nuclear translocation of TAB2 and impedes pyroptosis in colon cancer

Colon cancer (CC) is one of the most prevalent malignant tumors and is associated with a poor prognosis. Pyroptosis plays an important role in colon cancer. However, the specific regulatory mechanisms require further exploration. Previous studies have confirmed the association between PIAS1 and NF-κB signaling pathway. Notably, the link between PIAS1 and pyroptosis has not been reported. Circular non-coding RNAs (circRNAs) play a crucial role in cancer progression and the proteins encoded by circRNAs often substitute for host genes and play a significant role in the progression of cancer. The characteristics of circPIAS1 were identified through polymerase chain reaction (PCR) assays and RNase R tolerance assays. The subcellular localization of circPIAS1 was analyzed using fluorescence in situ hybridization (FISH), while its protein-coding capability was assessed through LC–MS/MS and immunofluorescence (IF). In vitro, RNA sequencing (RNA-seq) and western blot were conducted using siRNAs and plasmids transfection of cells to elucidate the potential role and mechanism of circPIAS1-108aa in colon cancer (CC). Immunoprecipitation (IP), and IP-mass spectrometry (IP-MS) were employed to investigate the proteins interacting with circPIAS1-108aa. Additionally, AlphaFold3 was utilized to predict the interaction sites. The proliferation and development of tumor cells in nude mice were assessed through lentiviral transfection in vivo. CircPIAS1 was transcribed from the PIAS1 gene and formed by back-splicing of exons 3–6 of the linear transcript. LC–MS/MS demonstrated that circPIAS1 can encode a protein (circPIAS1-108aa) that was involved in the progression of CC. The immunohistochemistry (IHC) staining revealed that circPIAS1-108aa is significantly highly expressed in patient tissues. This highlights its pivotal role in CC pathogenesis. Functional assays demonstrated that circPIAS1-108aa promoted CC cell proliferation both in vitro and in vivo. Mechanistically, circPIAS1-108aa facilitated the nuclear import of TAB2 through physical interaction rather than post-translational modification, thereby inhibiting the activation of the NF-κB signaling pathway and the NOD-like receptor signaling pathway, which leads to the suppression of pyroptosis in CC cells. In this study, we identified that circPIAS1, derived from PIAS1 , can encode a protein (circPIAS1-108aa) to replace the parental gene in inhibiting pyroptosis in colon cancer cells. Mechanistically, we elucidated the regulatory effect of circPIAS1-108aa on NF-κB and NOD-like receptor signaling pathways, which is mediated by the physical binding of circPIAS1-108aa with TAB2 rather than post-translational modification. Taken together, this study highlights the role of circPIAS1 in inhibiting the pyroptosis of CC and suggests its potential application as a prognostic biomarker and a therapeutic target of CC.