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EZH2 endorses cell plasticity to non-small cell lung cancer cells facilitating mesenchymal to epithelial transition and tumour colonization

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Abstract

Reversible transition between the epithelial and mesenchymal states are key aspects of carcinoma cell dissemination and the metastatic disease, and thus, characterizing the molecular basis of the epithelial to mesenchymal transition (EMT) is crucial to find druggable targets and more effective therapeutic approaches in cancer. Emerging studies suggest that epigenetic regulators might endorse cancer cells with the cell plasticity required to conduct dynamic changes in cell state during EMT. However, epigenetic mechanisms involved remain mostly unknown. Polycomb Repressive Complexes (PRCs) proteins are well-established epigenetic regulators of development and stem cell differentiation, but their role in different cancer systems is inconsistent and sometimes paradoxical. In this study, we have analysed the role of the PRC2 protein EZH2 in lung carcinoma cells. We found that besides its described role in CDKN2A-dependent cell proliferation, EZH2 upholds the epithelial state of cancer cells by repressing the transcription of hundreds of mesenchymal genes. Chemical inhibition or genetic removal of EZH2 promotes the residence of cancer cells in the mesenchymal state during reversible epithelial–mesenchymal transition. In fitting, analysis of human patient samples and tumour xenograft models indicate that EZH2 is required to efficiently repress mesenchymal genes and facilitate tumour colonization in vivo. Overall, this study discloses a novel role of PRC2 as a master regulator of EMT in carcinoma cells. This finding has important implications for the design of therapies based on EZH2 inhibitors in human cancer patients.

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Fig. 1: EZH2 binds and represses mesenchymal genes in lung carcinoma cells.
Fig. 2: TGF-β-induced EMT is reversible in A549 cells.
Fig. 3: Binding of EZH2 to target promoters remains constant during EMT in A549 cells.
Fig. 4: EZH2 represses a large set of mesenchymal genes during EMT–MET in A549 cells.
Fig. 5: EZH2-null A549 cells acquire mesenchymal features but remain responsive to TGF-β stimulation.
Fig. 6: EZH2-null A549 cells display reduced tumor colonization capacity in xenograft assays.

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Data availability

Datasets are available at GEO-NCBI with accession number GSE180067.

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Acknowledgements

We are very grateful to Diego de Miguel Perez and Dra. Maria Jose Serrano for providing cell lines and technical advice. We thank Dra. Aurora Serrano, Natasa Vukovic, core facilities at GENYO and the Animal Experimentation Unit at University of Granada for excellent technical support. We also thank the genomics unit at the CRG for assistance with RNA-seq and ChIP-seq experiments.

Funding

CGL was funded by the Consejería de Salud y Familias, Junta de Andalucía (RH-0139-2020) and SG-P is funded by Instituto de Salud Carlos III (CP19/00029, PI15/00336, PI19/01533). JAM is supported by RTI2018.101309B-C22 funded by MCIN/AEI/10.13039/501100011033/FEDER “Una manera de hacer Europa” and by the Chair “Doctors Galera-Requena in cancer stem cell research”. PCS is funded by Ministerio de Ciencia e Innovación (grant PID2020-119032RB-I00) and FEDER/Junta de Andalucía-Consejería de Transformación Económica, Industria, Conocimiento y Universidades (grants P20_00335 and B‐CTS‐40‐UGR20). The Landeira lab is supported by the Spanish ministry of science and innovation (PID2019-108108-100, EUR2021-122005), the Andalusian regional government (PC-0246-2017, PIER-0211-2019, PY20_00681) and the University of Granada (A-BIO-6-UGR20) grants.

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Author notes

  1. These authors contributed equally: Amador Gallardo, Aldara Molina.

Authors and Affiliations

  1. Centre for Genomics and Oncological Research (GENYO), Avenida de la Ilustración 114, 18016, Granada, Spain

    Amador Gallardo, Aldara Molina, Helena G. Asenjo, Lourdes Lopez-Onieva, Jordi Martorell-Marugán, Mencia Espinosa-Martinez, Carmen Griñan-Lison, Juan Carlos Alvarez-Perez, Francisca E. Cara, Pedro Carmona-Sáez, Pedro P. Medina, Sergio Granados-Principal, Antonio Sánchez-Pozo & David Landeira

  2. Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, University of Granada, Granada, Spain

    Amador Gallardo, Aldara Molina, Helena G. Asenjo, Mencia Espinosa-Martinez, Sergio Granados-Principal, Antonio Sánchez-Pozo & David Landeira

  3. Instituto de Investigación Biosanitaria ibs.GRANADA, Granada, Spain

    Amador Gallardo, Aldara Molina, Helena G. Asenjo, Lourdes Lopez-Onieva, Mencia Espinosa-Martinez, Carmen Griñan-Lison, Juan Carlos Alvarez-Perez, Saul A. Navarro-Marchal, Pedro P. Medina, Juan Antonio Marchal, Sergio Granados-Principal & David Landeira

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

    Lourdes Lopez-Onieva, Juan Carlos Alvarez-Perez & Pedro P. Medina

  5. Department of Statistics, Faculty of Sciences, University of Granada, Granada, Spain

    Jordi Martorell-Marugán & Pedro Carmona-Sáez

  6. Data Science for Health Research Unit, Fondazione Bruno Kessler, Trento, Italy

    Jordi Martorell-Marugán

  7. UGC de Oncología Médica, Complejo Hospitalario de Jaen, 23007, Jaen, Spain

    Carmen Griñan-Lison

  8. Department of Applied Physics, Faculty of Science, University of Granada, 18071, Granada, Spain

    Saul A. Navarro-Marchal

  9. Biopathology and Regenerative Medicine Institute (IBIMER), Centre for Biomedical Research (CIBM), University of Granada, 18016, Granada, Spain

    Saul A. Navarro-Marchal & Juan Antonio Marchal

  10. Excellence Research Unit Modelling Nature (MNat), University of Granada, 18016, Granada, Spain

    Saul A. Navarro-Marchal & Juan Antonio Marchal

  11. Cancer Research UK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, EH4 2XU, Edinburgh, UK

    Saul A. Navarro-Marchal

  12. Department of Human Anatomy and Embryology, School of Medicine, University of Granada, Granada, Spain

    Juan Antonio Marchal

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  1. Amador Gallardo
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  2. Aldara Molina
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Contributions

DL designed and conceptualized the study. DL and AG designed experiments. AG, AM, HGA, LLO, FEC and MEM performed and analysed experiments. CGL, JCAV and SANM performed xenograft assays. JMM performed bioinformatic analyses. PCS, SGP, LLO, JAM, PPM, ASP and DL provided scientific advice and resources. DL, LLO and ASP obtained funding and supervised research.

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Correspondence to David Landeira.

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Gallardo, A., Molina, A., Asenjo, H.G. et al. EZH2 endorses cell plasticity to non-small cell lung cancer cells facilitating mesenchymal to epithelial transition and tumour colonization. Oncogene 41, 3611–3624 (2022). https://doi.org/10.1038/s41388-022-02375-x

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