title: Pharmacological activation of p53 triggers anticancer innate immune response through induction of ULBP2.
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 is promising strategy 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.
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Hai
authors.initials: H
authors.lastname: Li
authors.forename: Tadepally
authors.initials: T
authors.lastname: Lakshmikanth
authors.forename: Cinzia
authors.initials: C
authors.lastname: Garofalo
authors.forename: Martin
authors.initials: M
authors.lastname: Enge
authors.forename: Clemens
authors.initials: C
authors.lastname: Spinnler
authors.forename: Andrea
authors.initials: A
authors.lastname: Anichini
authors.forename: Laszlo
authors.initials: L
authors.lastname: Szekely
authors.forename: Klas
authors.initials: K
authors.lastname: Kärre
authors.forename: Ennio
authors.initials: E
authors.lastname: Carbone
authors.forename: Galina
authors.initials: G
authors.lastname: Selivanova
mesh_terms: D045744:Cell Line, Tumor; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism; D019175:DNA Methylation; D005663:Furans / Q000494:pharmacology; D058851:GPI-Linked Proteins / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000378:metabolism / Q000502:physiology; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000037:antagonists & inhibitors / Q000378:metabolism; D009369:Neoplasms / Q000276:immunology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D005663:Furans; D058851:GPI-Linked Proteins; D036341:Intercellular Signaling Peptides and Proteins; C527085:KLRK1 protein, human; D055655:NK Cell Lectin-Like Receptor Subfamily K; C118989:NSC 652287; D016159:Tumor Suppressor Protein p53; C423230:ULBP2 protein, human; D004248:DNA (Cytosine-5-)-Methyltransferases