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

研究成果: Article査読

33 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)48-53
ページ数6
ジャーナルBiochemical and Biophysical Research Communications
390
1
DOI
出版ステータスPublished - 04-12-2009
外部発表はい

All Science Journal Classification (ASJC) codes

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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