Journal Article

Plakophilin 1 enhances MYC translation, promoting squamous cell lung cancer

Andrades Alvaro, Díaz-Cano Inés, Alvarez-Perez, Juan Carlos, Baliñas-Gavira Carlos, Boyero, Laura, Fárez-Vidal, María Esther, Medina, Pedro P, Martin-Padron, Joel, Coira, Isabel F, Peinado, Paola, Rodriguez, Maria Isabel

2020

Overview

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 knockout 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 posttranscriptional 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 anticancer target.

• Publisher: Nature Publishing Group
• Subject: 5' Untranslated Regions / Cell growth / Cell proliferation / Cell survival / CRISPR / Desmosomes / Gene families / Initiation complex / Kinases / Lung cancer / Myc protein / Post-transcription / Proteomics / Therapeutic targets / Translation / Translation initiation / Tumor suppressor genes / Xenografts