title: Impaired PIASy-Tip60 signaling weakens activation of p53 in melanoma.
abstract: The tumor suppressor p53 plays a central role in preventing tumor development by promoting transcription of genes that stall cell cycle and induce cell death. Although the majority of melanomas express wild-type p53, the molecular mechanisms that impede its activation remain unclear. We previously reported that the SUMO E3 ligase PIASy and the histone acetyltransferase Tip60 signaling cascade promote p53-dependent autophagy and apoptosis. We hypothesized that impairment in this signaling attenuates p53, thus disabling its apoptotic function in melanoma. Here, we show that human melanoma patient samples and cell lines maintain p53 expression but PIASy and/or Tip60 are frequently lost. We observed dysregulation of Tip60-mediated p53 transcription program in melanoma cell lines. Reconstitution of PIASy and Tip60 in melanoma cells increased genotoxic stress-induced apoptosis. Our study provides a clinical link of how sumoylation signaling may activate p53-mediated cell death in melanoma.
authors.affiliation: Departments of Dermatology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Lakhter
authors.forename: Sriramana
authors.initials: S
authors.lastname: Kanginakudru
authors.forename: Simon
authors.initials: S
authors.lastname: Warren
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Touloukian
authors.forename: Raymond E
authors.initials: RE
authors.lastname: Boissy
authors.forename: Samisubbu R
authors.initials: SR
authors.lastname: Naidu
mesh_terms: D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D000074443:Lysine Acetyltransferase 5; D008545:Melanoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000075223:Poly-ADP-Ribose Binding Proteins; D050828:Protein Inhibitors of Activated STAT / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: C485891:PIAS4 protein, human; D000075223:Poly-ADP-Ribose Binding Proteins; D050828:Protein Inhibitors of Activated STAT; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051548:Histone Acetyltransferases; C098489:KAT5 protein, human; D000074443:Lysine Acetyltransferase 5