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.
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We thank the PhD program in Biochemistry and Molecular Biology of the University of Granada and also Montse Sanchez-Céspedes for the critical read of the paper.
J-M-P and LB were supported by fellowships from Fundación Anticancer San Francisco Javier y Santa Cándida/UGR. AA was supported by a PhD FPU fellowship (FPU17/00067). PP was supported by a PhD “La Caixa Foundation” LCF/BQ/DE15/10360019 Fellowship. IFC was supported by a PhD FPI-fellowship (BES-2013-064596). JCA-P is supported by a Marie Sklodowska Curie action (H2020-MSCA-IF-2018). CB and MIR were supported by Consejería de Sanidad de la Junta de Andalucía (Pl-0245-2017). MEF-V was supported by PAIDI program. Group BIO309. Junta de Andalucía, and Instituto de Salud Carlos III-Fondo de Investigación Sanitaria PI10/00198. PPM laboratory is funded by the Ministry of Economy of Spain (SAF2015-67919-R), Junta de Andalucía (P12-BIO-1655, PAIDI CTS-993), Francisco Cobos Foundation, FERO foundation, International Association for the study of lung cancer (IASLC) and Fundación Científica de la Asociación Española Contra el Cáncer (Lab AECC-2018). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the paper. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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Martin-Padron, J., Boyero, L., Rodriguez, M.I. et al. Plakophilin 1 enhances MYC translation, promoting squamous cell lung cancer. Oncogene (2019). https://doi.org/10.1038/s41388-019-1129-3