Abstract

Colorectal cancer remains a major cause of cancer-related mortality worldwide, underscoring the critical need for novel biomarkers and effective therapeutic targets. In this study, we identify the long non-coding RNA AC004854.2 as significantly up-regulated in colorectal cancer tissues and strongly associated with poor clinical prognosis. Mechanistic analyses reveal that AC004854.2 competitively interacts with PUF60, leading to the disruption of the PUF60–FUBP1 repressor complex at the far-upstream element (FUSE) of the c-MYC promoter, thereby enhancing c-MYC transcription. Upstream, SRY-box transcription factor 4 (SOX4) binds to the promoter region of AC004854.2 and activates its transcriptional expression. Functional studies demonstrate that AC004854.2 promotes colorectal cancer cell proliferation, G1-phase cell cycle arrest, migration, and invasion in vitro , and enhances tumor growth in vivo . Notably, these oncogenic effects are attenuated by treatment with IZCZ-3, a selective c-MYC inhibitor, indicating their dependence on c-MYC signaling. In two independent clinical cohorts, elevated AC004854.2 expression is positively correlated with increased levels of c-MYC, CCND2, and CDK4, and serves as an independent predictor of reduced overall survival. Collectively, our findings delineate a previously uncharacterized signaling axis of SOX4/AC004854.2/PUF60/c-MYC that functions in parallel to the canonical WNT/β-catenin pathway to amplify promoter-proximal c-MYC transcription. These results support AC004854.2 as a potential prognostic biomarker and a candidate therapeutic target in colorectal cancer.