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Plakophilin 1 enhances MYC translation, promoting squamous cell lung cancer

Oncogene volume 39, pages 5479–5493 (2020)Cite this article

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A Correction to this article was published on 13 January 2020

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Abstract

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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Fig. 1: Morphology, viability, cell-colony analysis, cell cycle progression, p21 expression, and apoptosis determination of SK-MES-1 cells after PKP1 silencing.
Fig. 2: Ectopic expression of PKP1 in NCI-H2170 SqCLC cell line after pLVX-IRES-ZsGreen1-PKP1A plasmid transduction.
Fig. 3: Analysis of knockout clones #1 and #2 in SK-MES-1 cell line using the CRISPR-Cas9 system.
Fig. 4: Tumor xenograft assay of PKP1 knockout cells on immunodeficient NSG mice.
Fig. 5: Top-scoring MYC-related gene sets in a gene set enrichment analysis (GSEA) of the results of the transcriptome profiling in SK-MES-1 PKP1 knockdown cells and their PKP1-expressing controls.
Fig. 6: PKP1/MYC functional relationship.

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Data availability

The microarray data have been deposited on Gene Expression Omnibus (GEO) under the accession number GSE106770.

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Acknowledgements

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.

Funding

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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Author notes

  1. Lead contact: Pedro P. Medina

  2. These authors contributed equally: Joel Martin-Padron, Laura Boyero

Authors and Affiliations

  1. Centre for Genomics and Oncological Research (GENYO), Granada, Spain

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

  2. Department of Biochemistry and Molecular Biology III, University of Granada, Granada, Spain

    Joel Martin-Padron, Laura Boyero, Inés Díaz-Cano & María Esther Fárez-Vidal

  3. Institute for Biomedical Research ibs. Granada, University Hospital Complex of Granada/University of Granada, Granada, Spain

    Joel Martin-Padron, Inés Díaz-Cano, María Esther Fárez-Vidal & Pedro P. Medina

  4. Department of Biochemistry and Molecular Biology I, University of Granada, Granada, Spain

    Maria Isabel Rodriguez, Alvaro Andrades, Paola Peinado, Carlos Baliñas-Gavira, Juan Carlos Alvarez-Perez, Isabel F. Coira & Pedro P. Medina

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Contributions

JM-P, LB, MIR, PP, ID-C, CB, IFC, JCA-P performed and validated the experimental data. AA performed most of bioinformatics and statistical analysis. PPM and MEF-V wrote the paper, reviewed and edited the manuscript and provided conceptualization, validation, supervision, expertise and feedback. MEF-V and PPM, participated in the funding acquisition and project administration.

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Correspondence to María Esther Fárez-Vidal or Pedro P. Medina.

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This project has been approved by the institutional ethical committee of the University of Granada.

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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 39, 5479–5493 (2020). https://doi.org/10.1038/s41388-019-1129-3

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