Oncogenic role of plakophilin-1 in non-small cell lung cancer

  1. MARTÍN PADRÓN, JOEL
unter der Leitung von:
  1. Pedro Pablo Medina Vico Doktorvater
  2. María Esther Farez Vidal Doktormutter

Universität der Verteidigung: Universidad de Granada

Fecha de defensa: 30 von Januar von 2020

Gericht:
  1. Antonio Sánchez Pozo Präsident
  2. Jesús Manuel Torres de Pinedo Sekretär
  3. Valentina Iadevaia Vocal
  4. Juan Carlos Rodriguez Manzaneque Escribano Vocal
  5. María Teresa Valero Griñán Vocal
Fachbereiche:
  1. BIOQUÍMICA Y BIOLOGÍA MOLECULAR I

Art: Dissertation

Zusammenfassung

Plakophilin 1 (PKP1) is a member of the arm-repeat (armadillo) and plakophilin gene families and it is an essential component of the desmosomes. Although desmosomes have generally been associated with tumor suppressor functions, we have consistently observed that PKP1 is among the top overexpressed proteins in squamous cell lung cancer. To explore this paradox, we developed in vivo and in vitro functional models of PKP1 gain/loss in squamous cell lung cancer. CRISPR-Cas9 PKP1 knock-out severely impaired cell proliferation, but it increased cell dissemination. In addition, PKP1 overexpression increased cell proliferation, cell survival and in vivo xenograft engraftment. We further investigated the molecular mechanism of the mainly oncogenic function of PKP1 by combining transcriptomics, proteomics and protein-nucleic acid interaction assays. Interestingly, we found that PKP1 enhances MYC translation in collaboration with the translation initiation complex by binding to the 5’-UTR of MYC mRNA. We propose PKP1 as an oncogene in SqCLC and a novel post-transcriptional regulator of MYC. PKP1 may be a valuable diagnostic biomarker and potential therapeutic target for SqCLC. Importantly, PKP1 inhibition may indirectly target MYC, a primary anti-cancer target.