Differential expression of MHC class II molecules in highly metastatic breast cancer cells is mediated by the regulation of the CIITA transcription: Implication of CIITA in tumor and metastasis development

Bo Shi, Antònia Vinyals, Pedro Alia, Cristina Broceño, Feisong Chen, Marc Adrover, Carme Gelpi, Janet E. Price, Àngels Fabra*

*Corresponding author for this work

Research output: Contribution to journalArticle

36 Scopus citations

Abstract

We analyzed the differential gene expression between variants of MDA-MB-435 human breast cancer cell line that share an identical genetic background but have different metastatic ability. The major histocompatibility complex class II was found down-regulated in highly metastatic cells and correlated with MHC transactivator (CIITA) expression. Constitutive CIITA expression observed in poorly metastatic is driven by promoters III and IV of CIITA gene. Conversely, both promoters were ineffective in highly metastatic cells. The MHC class II and CIITA expression was restored in these cells upon stimulation with IFNγ or by the treatment with a hypomethylating agent. Both treatments induced USF-1 and IRF binding complexes to promoter IV but only IFNγ induced the binding of 435-Lung2 nuclear proteins to an ARE-1 site at the promoter III. Neither Southern blot nor bisulfite sequencing of promoter IV demonstrated strong hypermethylation of this promoter at the IFNγ-responsive elements such as GAS, E-box or IRF-1. We suggest that partial or hemimethylation of promoter IV is sufficient to silence the CIITA expression in highly metastatic cells and that this epigenetic mechanism is responsible for the lack of MHC-II expression. Forced CIITA expression restored the MHC-II antigen expression in 435-Lung2 cells and abrogates spontaneous lung metastasis in both SCID and nude mice but also affected the tumorigenicity in nude mice. The increase in NK cell infiltration in nude mice bearing CIITA-tumors correlated with sign of tumor cell apoptosis and the increase in the number of NK cells in the spleens, suggesting that NK cells might be responsible for the observed antitumor activity.

Original languageEnglish (US)
Pages (from-to)544-562
Number of pages19
JournalInternational Journal of Biochemistry and Cell Biology
Volume38
Issue number4
DOIs
StatePublished - Jan 26 2006

Keywords

  • 5-Aza-CR
  • CIITA
  • Differential expression metastasis
  • Epigenetic
  • INFγ
  • MHC class II
  • RAP-PCR

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology

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