Pharmacological activation of p53 triggers anticancer innate immune response through induction of ULBP2

Hai Li, Tadepally Lakshmikanth, Cinzia Garofalo, Martin Enge, Clemens Spinnler, Andrea Anichini, Laszlo Szekely, Klas Kärre, Ennio Carbone, Galina Selivanova

Research output: Contribution to journalArticlepeer-review

Abstract

Escape of tumor cells from cell-intrinsic barrier mediated by tumor suppressors and cell-extrinsic barrier mediated by the immune system is crucial for tumorigenesis. Growing evidence suggests that reactivation of tumor suppressor function or restoration of anticancer immunity are promising strategies for anticancer therapy due to their high potential to combat cancer. p53, a key tumor suppressor, represses tumorigenesis by eliciting growth arrest, apoptosis or senescence in cancer cells. Here, we unravel that, apart from these cell-autonomous effects, p53 activates the innate immune response against cancer cells. Our results show that pharmacological reactivation of p53 can stimulate the expression of ULPB2, a ligand for NK cell activating receptor NKG2D in human tumor cells of different origin, which enhance the susceptibility of tumor cells to NK cell-mediated killing. The molecular mechanism controlling ULPB2 expression by p53 is neither ATM/ ATR- nor caspase-dependent. Using several approaches, we identified p53 as a direct transcriptional regulator of ULBP2 and found a p53 response element within ULBP2 gene, which confers the p53 regulation. Furthermore, we demonstrated that demethylation of p53-binding region within ULBP2 gene was required for p53-dependent induction of ULPB2, which can be achieved via repression of DNA methyltransferases (DNMTs) by p53. This molecular evidence for the direct control of immunosurveillance by p53 links tumor suppressor activation to innate immune stimuli and provides a possibility to integrate cell-extrinsic and -intrinsic defenses against tumorigenesis by pharmacological activation of p53, which may increase the probability to achieve a durable therapeutic success.

Original languageEnglish
Pages (from-to)3346-3358
Number of pages13
JournalCell Cycle
Volume10
Issue number19
DOIs
Publication statusPublished - Oct 1 2011

Keywords

  • Cancer immunotherapy
  • DNA methylation
  • p53
  • Pharmacological activation
  • Tumor suppressor

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Developmental Biology

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