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

  1. Santosh Kumar Gothwal
  2. Pieta K. Mattila
  3. Jacqueline H Barlow
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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

    Article activity feed

    1. Version published to 10.1101/2024.08.31.609994v2 on bioRxiv
    2. Version published to 10.1101/2024.08.31.609994v1 on bioRxiv