Smurf2 suppresses B-cell proliferation and lymphomagenesis by mediating ubiquitination and degradation of YY1

Nat Commun. 2013:4:2598. doi: 10.1038/ncomms3598.

Abstract

About half of patients with diffuse large B-cell lymphoma (DLBCL) do not respond to or relapse soon after the standard chemotherapy, indicating a critical need to better understand the specific pathways perturbed in DLBCL for developing effective therapeutic approaches. Mice deficient in the E3 ubiquitin ligase Smurf2 spontaneously develop B-cell lymphomas that resemble human DLBCL with molecular features of germinal centre or post-germinal centre B cells. Here we show that Smurf2 mediates ubiquitination and degradation of YY1, a key germinal centre transcription factor. Smurf2 deficiency enhances YY1-mediated transactivation of c-Myc and B-cell proliferation. Furthermore, Smurf2 expression is significantly decreased in primary human DLBCL samples, and low levels of Smurf2 expression correlate with inferior survival in DLBCL patients. The Smurf2-YY1-c-Myc regulatory axis represents a novel pathway perturbed in DLBCL that suppresses B-cell proliferation and lymphomagenesis, suggesting pharmaceutical targeting of Smurf2 as a new therapeutic paradigm for DLBCL.

Publication types

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

MeSH terms

  • Animals
  • B-Lymphocytes / metabolism
  • B-Lymphocytes / pathology
  • Cell Line, Tumor
  • Cell Proliferation
  • Gene Expression Regulation, Neoplastic*
  • Germinal Center / metabolism
  • Germinal Center / pathology
  • Humans
  • Lymphocyte Activation
  • Lymphoma, Large B-Cell, Diffuse / genetics*
  • Lymphoma, Large B-Cell, Diffuse / metabolism
  • Lymphoma, Large B-Cell, Diffuse / pathology
  • Mice
  • Mice, Knockout
  • Proteasome Endopeptidase Complex / metabolism
  • Proteolysis
  • Proto-Oncogene Proteins c-myc / genetics*
  • Proto-Oncogene Proteins c-myc / metabolism
  • Signal Transduction
  • Transcription, Genetic
  • Ubiquitin-Protein Ligases / deficiency
  • Ubiquitin-Protein Ligases / genetics*
  • Ubiquitin-Protein Ligases / metabolism
  • Ubiquitination
  • YY1 Transcription Factor / genetics*
  • YY1 Transcription Factor / metabolism

Substances

  • Myc protein, mouse
  • Proto-Oncogene Proteins c-myc
  • YY1 Transcription Factor
  • Yy1 protein, mouse
  • SMURF2 protein, human
  • Smurf2 protein, mouse
  • Ubiquitin-Protein Ligases
  • Proteasome Endopeptidase Complex