RT Journal Article
SR Electronic
T1 Distal super-enhancer drives aberrant <em>CXCL13</em> expression in Cancer cells driving growth and p53 dysregulation via CXCR5-CXCL13 axis
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2024.08.31.609994
DO 10.1101/2024.08.31.609994
A1 Gothwal, Santosh Kumar
A1 Mattila, Pieta K.
A1 Barlow, Jacqueline H
YR 2024
UL http://biorxiv.org/content/early/2024/09/04/2024.08.31.609994.abstract
AB 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 PointsSuper-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+ cellsCXCR5-CXCL13 axis impairs p53 target gene expression and promotes tumor growthHighlightsAberrant CXCL13 expression in hematological and solid cancersChemotherapeutic treatment of cancer cells promotes CXCL13 and CXCR5 expressionDistal super-enhancer on CCNG2 interacts with CXCL13 promoterCXCL13 expression in B-lymphomas prevents CXCR5-dependent migrationCXCR5-CXCL13 axis encounters p53 function in hematological and solid cancer cellsCompeting Interest StatementThe authors have declared no competing interest.