High-resolution chromatin immunoprecipitation (ChIP) sequencing reveals novel binding targets and prognostic role for SOX11 in mantle cell lymphoma

Oncogene. 2015 Mar 5;34(10):1231-40. doi: 10.1038/onc.2014.44. Epub 2014 Mar 31.

Abstract

Sex determining region Y-box 11 (SOX11) expression is specific for mantle cell lymphoma (MCL) as compared with other non-Hodgkin's lymphomas. However, the function and direct-binding targets of SOX11 in MCL are largely unknown. We used high-resolution chromatin immunoprecipitation sequencing to identify the direct target genes of SOX11 in a genome-wide, unbiased manner and elucidate its functional significance. Pathway analysis identified WNT, PKA and TGF-beta signaling pathways as significantly enriched by SOX11-target genes. Quantitative chromatin immunoprecipitation sequencing and promoter reporter assays confirmed that SOX11 directly binds to individual genes and modulates their transcription activities in these pathways in MCL. Functional studies using RNA interference demonstrate that SOX11 directly regulates WNT in MCL. We analyzed SOX11 expression in three independent well-annotated tissue microarrays from the University of Wisconsin (UW), Karolinska Institute and British Columbia Cancer Agency. Our findings suggest that high SOX11 expression is associated with improved survival in a subset of MCL patients, particularly those treated with intensive chemotherapy. Transcriptional regulation of WNT and other biological pathways affected by SOX11-target genes may help explain the impact of SOX11 expression on patient outcomes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols
  • Binding Sites
  • Cell Cycle Checkpoints
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Survival / drug effects
  • Chromatin Immunoprecipitation
  • Gene Expression
  • Gene Expression Regulation, Neoplastic
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Lymphoma, Mantle-Cell / drug therapy
  • Lymphoma, Mantle-Cell / genetics*
  • Lymphoma, Mantle-Cell / metabolism*
  • Lymphoma, Mantle-Cell / mortality
  • Nucleotide Motifs
  • Prognosis
  • Protein Binding
  • SOXC Transcription Factors / genetics
  • SOXC Transcription Factors / metabolism*
  • Signal Transduction
  • Transcription, Genetic
  • Wnt Proteins / metabolism
  • Wnt Signaling Pathway
  • beta Catenin / metabolism

Substances

  • SOX11 protein, human
  • SOXC Transcription Factors
  • Wnt Proteins
  • beta Catenin