The DCBLD2 super-enhancer drives colorectal cancer progression through FOSL2/JUND-mediated activation of the CD146/AKT/TNFRSF6B pathway.

Super-enhancers are clusters of cis-regulatory elements that sustain the expression of cell-identity genes. Their aberrant activation or dysfunction constitutes a hallmark of malignant cellular transformation, which frequently rewires oncogenic transcriptional programs to support uncontrolled cell proliferation and metastatic potential. However, the functions and epigenetic regulation mechanisms of colorectal cancer specific super-enhancers remain poorly understood, and few studies have focused on dissecting how tumor enriched super-enhancers mediate downstream oncogenic signaling in CRC. By integrating multi-omics sequencing data, we identified a highly active super-enhancer in colorectal cancer, termed DCBLD2-SE. Through luciferase reporter assays, the SE3-2 subregion was identified as the minimal functional core of this super-enhancer. Mechanistic studies confirmed that transcription factors of the activator protein-1 family (FOSL2 and JUND) can bind directly to the SE3-2 cis-regulatory element, synergistically regulating local chromatin remodeling and strongly driving the upregulation of the target gene DCBLD2. Following knockout of the DCBLD2-SE core region, the malignant proliferative capacity of colorectal cancer cells decreased significantly, and the growth of xenograft tumors in vivo was markedly inhibited. Functionally, DCBLD2-SE facilitates tumor progression through a DCBLD2-dependent CD146/AKT/TNFRSF6B signaling axis. Clinically, high expression of DCBLD2 correlates with malignant metastasis and poor overall survival in patients with colorectal cancer. In summary, this study uncovers a previously undescribed DCBLD2-centered regulatory cascade that promotes colorectal cancer initiation and progression. DCBLD2-SE and its binding transcription factor activator protein-1 represent promising prognostic biomarkers and actionable therapeutic targets for colorectal cancer.