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 PointsO_LISuper-enhancer near CCNG2 region interacts with CXCL13-TSS driving CXCL13 in cancers. C_LIO_LIAberrant CXCL13 prevents CXCR5-mediated migration of B-lymphomas and promotes growth and p53 dysregulation in CXCR5+ cells C_LIO_LICXCR5-CXCL13 axis impairs p53 target gene expression and promotes tumor growth C_LI O_FIG O_LINKSMALLFIG WIDTH=171 HEIGHT=200 SRC="FIGDIR/small/609994v2_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@abf94corg.highwire.dtl.DTLVardef@7bfd55org.highwire.dtl.DTLVardef@351645org.highwire.dtl.DTLVardef@1493e62_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIAberrant CXCL13 expression in hematological and solid cancers C_LIO_LIChemotherapeutic treatment of cancer cells promotes CXCL13 and CXCR5 expression C_LIO_LIDistal super-enhancer on CCNG2 interacts with CXCL13 promoter C_LIO_LICXCL13 expression in B-lymphomas prevents CXCR5-dependent migration C_LIO_LICXCR5-CXCL13 axis encounters p53 function in hematological and solid cancer cells C_LI