Distal super-enhancer drives aberrant CXCL13 expression in Cancer cells driving growth and p53 dysregulation via CXCR5-CXCL13 axis

Abstract The CXCL13 chemokine plays a crucial role in guiding B cell migration to the light zones (LZs) during the germinal center (GC) reaction. While CXCL13 expression is absent in most cell types, aberrant amplification of the CXCR5-CXCL13 signaling is observed in various cancers, including germinal center-derived B-lymphomas (GCDBL), colorectal adenocarcinoma (COAD), and liver hepatocellular carcinoma (LIHC). However, the molecular mechanisms underlying abnormal CXCL13 transcription in cancer cells and its functional consequences remain elusive. We identify DNA-CpG methylation binding protein 1 (MBD1) as a suppressor of CXCL13 expression. Chromosomal conformation capture (3C) analysis reveals a distal super-enhancer located near CCNG2 that interacts with the CXCL13 promoter in GCDBL, suggesting that enhancer-hijacking drives the aberrant expression. Our functional validation demonstrates that CXCR5-CXCL13 signaling suppresses p53 and its target genes in GCDBLs, COAD, and LIHC. Notably, CXCL13 in the GCDBL cell line Raji disrupts CXCR5-mediated migration, a mechanism essential for (light zone) LZ-entry and affinity maturation of GC B cells. These findings highlight the dual role of the CXCR5-CXCL13 axis in immune response and cancer proliferation. Key Points Super-enhancer near CCNG2 region interacts with CXCL13-TSS driving CXCL13 in cancers. Aberrant CXCL13 prevents CXCR5-mediated migration of B-lymphomas and promotes growth and p53 dysregulation in CXCR5+ cells CXCR5-CXCL13 axis impairs p53 target gene expression and promotes tumor growth Abstract Figure Highlights Aberrant CXCL13 expression in hematological and solid cancers Chemotherapeutic treatment of cancer cells promotes CXCL13 and CXCR5 expression Distal super-enhancer on CCNG2 interacts with CXCL13 promoter CXCL13 expression in B-lymphomas prevents CXCR5-dependent migration CXCR5-CXCL13 axis encounters p53 function in hematological and solid cancer cells