Escape mechanisms from antibody therapy to lymphoma cells: Downregulation of CD20 mRNA by recruitment of the HDAC complex and not by DNA methylation

Takumi Sugimoto, Akihiro Tomita, Junji Hiraga, Kazuyuki Shimada, Hitoshi Kiyoi, Tomohiro Kinoshita, Tomoki Naoe

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Although rituximab is a critical monoclonal antibody therapy for CD20-positive B-cell lymphomas, rituximab resistance showing a CD20-negative phenotypic change has been a considerable clinical problem. Here we demonstrate that CD20 mRNA and protein expression is repressed by recruitment of a histone deacetylase protein complex to the MS4A1 (CD20) gene promoter in CD20-negative transformed cells after treatment with rituximab. CD20 mRNA and protein expression were stimulated by decitabine (5-Aza-dC) in CD20-negative transformed cells, and was enhanced by trichostation A (TSA). Immunoblotting indicated that DNMT1 expression was first downregulated 1 day after treatment with 5-Aza-dC, but IRF4 and Pu.1, the transcriptional regulators of MS4A1, were still expressed with or without 5-Aza-dC. Interestingly, CpG methylation of the MS4A1 promoter was not observed in CD20-negative transformed cells without 5-Aza-dC. A chromatin immunoprecipitation (ChIP) assay indicated that the Sin3A-HDAC1 co-repressor complex was recruited to the promoter and dissociated from the promoter with 5-Aza-dC and TSA, resulting in histone acetylation. Under these conditions, IRF4 and Pu.1 were continually recruited to the promoter with or without 5-Aza-dC and TSA. These results suggest that recruitment of the Sin3A-HDAC1 complex is related to downregulation of CD20 expression in CD20-negative B-cells after treatment with rituximab.

Original languageEnglish
Pages (from-to)48-53
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume390
Issue number1
DOIs
Publication statusPublished - 04-12-2009

All Science Journal Classification (ASJC) codes

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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