Abstract
AbstractThe CXCL13 chemokine plays a crucial role in guiding B cell migration to the light zones (LZs) during the germinal center (GC) reaction. WhileCXCL13expression 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 abnormalCXCL13transcription in cancer cells and its functional consequences remain elusive. We identify DNA-CpG methylation binding protein 1 (MBD1) as a suppressor ofCXCL13expression. Chromosomal conformation capture (3C) analysis reveals a distal super-enhancer located nearCCNG2that interacts with theCXCL13promoter 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 PointsSuper-enhancer nearCCNG2region interacts withCXCL13-TSSdriving CXCL13 in cancers.Aberrant CXCL13 prevents CXCR5-mediated migration of B-lymphomas and promotes growth and p53 dysregulation in CXCR5+ cellsCXCR5-CXCL13 axis impairs p53 target gene expression and promotes tumor growthAbstract FigureHighlightsAberrantCXCL13expression in hematological and solid cancersChemotherapeutic treatment of cancer cells promotesCXCL13andCXCR5expressionDistal super-enhancer onCCNG2interacts withCXCL13promoterCXCL13 expression in B-lymphomas prevents CXCR5-dependent migrationCXCR5-CXCL13 axis encounters p53 function in hematological and solid cancer cells
Publisher
Cold Spring Harbor Laboratory