Abstract 1346: MYC-YTHDF1-IRF2BP2 axis drive tumor metastasis and immune escape in CMS2 colorectal cancer

Abstract Colorectal cancer (CRC) has a particularly low 5-year survival rate in patients with metastases. Based on the molecular and pathological characteristics of CRC, the disease can be classified into four consensus molecular subtypes (CMS1-4), with CMS2 being the most prevalent. CMS2 colorectal cancer is characterized by sustained activation of MYC, which drives the elevated expression of the m6A-binding protein YTHDF1. YTHDF1 (YTH m6A RNA-binding protein 1) is an m6A reader that facilitates mRNA translation and plays critical roles in tumor progression. However, its specific mechanisms in CRC remain poorly understood. Investigating the functional role of YTHDF1 could provide valuable insights for developing precise therapeutic approaches and combination treatment strategies for CRC.Interferon regulatory factor 2-binding protein 2 (IRF2BP2) encodes a member of the IRF2BP family of transcriptional regulators. IRF2BP2 is ubiquitously expressed in normal and tumor tissues across various organisms and is involved in regulating numerous cellular processes. However, its specific roles and mechanisms in CRC have not been elucidated. This study aims to systematically investigate the MYC-driven activation of the YTHDF1-IRF2BP2 axis and its impact on distant metastasis and immune evasion in CRC. Our findings aim to provide a foundation for identifying novel prognostic biomarkers and potential therapeutic targets for CRC.We analyzed YTHDF1 expression in CMS2 colorectal cancer using publicly available databases and patient samples from our center. Our findings revealed that CMS2 CRC exhibits elevated YTHDF1 expression, which is positively correlated with MYC expression. To validate the regulatory relationship between MYC and YTHDF1, we knocked down MYC in CRC cell lines. Western blot analysis demonstrated that MYC knockdown significantly suppressed YTHDF1 expression. Given that MYC is a downstream effector of the WNT signaling pathway, we treated CRC cells with the WNT activator Wnt3a, which resulted in increased MYC protein expression alongside enhanced YTHDF1 protein levels. Dual-luciferase reporter assays confirmed that MYC functions as a key transcriptional regulator, directly promoting YTHDF1 transcription.To identify downstream targets of YTHDF1, we performed RIP-Seq and proteomic profiling. Among the identified targets, IRF2BP2 was selected for further validation. Correlation analysis, Western blot, and RIP-PCR assays demonstrated that YTHDF1 regulates IRF2BP2 expression in an m6A-dependent manner. Functional studies and in vivo experiments showed that knocking down YTHDF1 or IRF2BP2 significantly inhibited CRC cell migration. These findings suggest that YTHDF1 promotes distant metastasis and immune evasion in CRC by regulating IRF2BP2, thereby contributing to CRC progression and malignancy. Citation Format: Ting Li, Yao Shang, Dongwen Chen, Chong Chen, Xinxin Huang, Yiran Bie, Zhengyu Wei, Zhengran Zhou, Chuling Hu, Xuanhui Liu, Yufeng Chen, Peishan Hu. MYC-YTHDF1-IRF2BP2 axis drive tumor metastasis and immune escape in CMS2 colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1346.