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

The CXCL13 chemokine expression is developmentally restricted to few cell types including T, B and dendritic cells. Aberrant amplification of CXCL13 expression and subsequent CXCR5-CXCL13 signaling occurs in multiple cancers, including germinal center (GC) derived B-lymphomas (GCDBL), and several solid cancers including of colorectal adenocarcinoma (COAD), and liver hepatocellular carcinoma (LIHC), however the molecular mechanisms underlying abnormal CXCL13 transcription in cancers remains elusive. Chromosomal conformation capture (3C) analysis reveals a distal super-enhancer located near CCNG2 that interacts with the CXCL13 promoter in GCDBL, suggesting enhancer-hijacking drives aberrant CXCL13 expression in cancer cells. Notably, internal CXCL13 in the GCDBL line Raji disrupts CXCR5-dependent migration, suggesting that elevated CXCL13 in GCDBL impairs light-zone migration, thus restricting GCDBL B-cell survival, a quality-control step preceding affinity maturation and high-affinity antibody production. Functional validation in cancer cells revealed CXCR5-CXCL13 signaling suppresses p53 and its target genes in COAD, LIHC and lymphoma cells. Together, these findings uncover a mechanism of aberrant CXCL13 transcription via super-enhancer hijacking in cancer cells that drives proliferation through p53 dysregulation in CXCR5-CXCL13-positive cancers, while CXCL13 expression in GCDBL can quality assure high affinity antibody production and B-lymphoma elimination during the GC reaction.