Abstract LB351: AXIN2 promotes WNT-target gene expression via cross-feedback between WNT and retinoic acid signaling pathways based on transcriptionally co-regulated components

Abstract APC mutation is the most common colorectal cancer (CRC) driver mutation, yet CRC patients carrying APC mutation have more favorable survival compared to those with only wild-type APC. Through NanoString transcriptome profiling, flow cytometry, western blot and Genomic Data Commons/The Cancer Genome Atlas (GDC/TCGA) RNA-seq data analysis, we discovered that instead of functioning as a negative regulator of WNT signaling, AXIN2 up-regulates WNT-target gene expression in CRC cells carrying mutant APC. To further explore the mechanism of this novel function of AXIN2, we hypothesize that AXIN2 up-regulates WNT-target gene expression through down-regulation of WNT-signaling activity and up-regulation of retinoic acid (RA) signaling activity in CRC cells with mutant APC. To test this hypothesis, we conducted ChIP-seq data analysis and identified a set of WNT- and RA - signaling pathway component genes that are transcriptionally co-regulated by both WNT- and RA-signaling activity. This finding led to our WNT- and RA- signaling transcriptional co-regulation model in which the sequential arrangement of TCF/LEF and RAR/RXR transcription factors determines the responsiveness of target gene transcription to WNT- or RA- signaling activity. Such difference in responsiveness was confirmed by CRC patient RNA-seq results from GDC/TCGA. We then implemented the transcriptional co-regulation model mathematically into an ordinary differential equation (ODE) model, and fitted the model to CRC patient RNA-seq data. Simulation results of our model are consistent with our western blot results on WNT-target gene expression in AXIN2-modulated CRC cell lines. Overall, our findings support our hypothesis that the AXIN2 positively regulates expression of WNT-target genes in CRC cells carrying mutant APC via cross-talk between WNT- and RA- signaling pathways, based on transcriptional co-regulation of pathway components. Citation Format: Chi Zhang, Gilberto Schleiniger, Caroline Facey, Lynn Opdenaker, Bruce Boman. AXIN2 promotes WNT-target gene expression via cross-feedback between WNT and retinoic acid signaling pathways based on transcriptionally co-regulated components [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB351.