NF-κB, and not MYCN, regulates MHC class I and endoplasmic reticulum aminopeptidases in human neuroblastoma cells

Matteo Forloni, Sonia Albini, Maria Zaira Limongi, Loredana Cifaldi, Renata Boldrini, Maria Rita Nicotra, Giuseppe Giannini, Pier Giorgio Natali, Patrizio Giacomini, Doriana Fruci

Research output: Contribution to journalArticlepeer-review

Abstract

Neuroblastoma (NB) is the most common solid extracranial cancer of childhood. Amplification and over-expression of the MYCN oncogene characterize the most aggressive forms and are believed to severely downregulate MHC class I molecules by transcriptional inhibition of the p50 NF-κB subunit. In this study, we found that in human NB cell lines, high MYCN expression is not responsible for low MHC class I expression because neither transfection-mediated overexpression nor small interfering RNA suppression of MYCN affects MHC class I and p50 levels. Furthermore, we identified NF-κB as the immediate upstream regulator of MHC class I because the p65 NF-κB subunit binds MHC class I promoter in chromatin immunoprecipitation experiments, and MHC class I expression is enhanced by p65 transfection and reduced by (a) the chemical NF-κB inhibitor sulfasalazine, (b) a dominant-negative IKBα gene, and (c) p65 silencing. Moreover, we showed that the endoplasmic reticulum aminopeptidases ERAP1 and ERAP2, which generate MHC class I binding peptides, are regulated by NF-κB, contain functional NF-κB-binding elements in their promoters, and mimic MHC class I molecules in the expression pattern. Consistent with these findings, nuclear p65 was detected in NB cells that express MHC class I molecules in human NB specimens. Thus, the coordinated downregulation of MHC class I, ERAP1, and ERAP2 in aggressive NB cells is attributable to a low transcriptional availability of NF-κB, possibly due to an unknown suppressor other than MYCN.

Original languageEnglish
Pages (from-to)916-924
Number of pages9
JournalCancer Research
Volume70
Issue number3
DOIs
Publication statusPublished - Feb 1 2010

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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