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

doi:10.1038/s41388-022-02375-x

. 2022 Jul;41(28):3611-3624.

doi: 10.1038/s41388-022-02375-x. Epub 2022 Jun 9.

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

Amador Gallardo^#^{1

2

3}, Aldara Molina^#^{1

2

3}, Helena G Asenjo^{1

2

3}, Lourdes Lopez-Onieva^{1

3

4}, Jordi Martorell-Marugán^{1

5

6}, Mencia Espinosa-Martinez^{1

2

3}, Carmen Griñan-Lison^{1

3

7}, Juan Carlos Alvarez-Perez^{1

3

4}, Francisca E Cara¹, Saul A Navarro-Marchal^{3

8

9

10

11}, Pedro Carmona-Sáez^{1

5}, Pedro P Medina^{1

3

4}, Juan Antonio Marchal^{3

9

10

12}, Sergio Granados-Principal^{1

2

3}, Antonio Sánchez-Pozo^{1

2}, David Landeira^{13

14

15}

Affiliations

¹ Centre for Genomics and Oncological Research (GENYO), Avenida de la Ilustración 114, 18016, Granada, Spain.
² Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, University of Granada, Granada, Spain.
³ Instituto de Investigación Biosanitaria ibs.GRANADA, Granada, Spain.
⁴ Department of Biochemistry and Molecular Biology I, Faculty of Sciences, University of Granada, Granada, Spain.
⁵ Department of Statistics, Faculty of Sciences, University of Granada, Granada, Spain.
⁶ Data Science for Health Research Unit, Fondazione Bruno Kessler, Trento, Italy.
⁷ UGC de Oncología Médica, Complejo Hospitalario de Jaen, 23007, Jaen, Spain.
⁸ Department of Applied Physics, Faculty of Science, University of Granada, 18071, Granada, Spain.
⁹ Biopathology and Regenerative Medicine Institute (IBIMER), Centre for Biomedical Research (CIBM), University of Granada, 18016, Granada, Spain.
¹⁰ Excellence Research Unit Modelling Nature (MNat), University of Granada, 18016, Granada, Spain.
¹¹ Cancer Research UK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, EH4 2XU, Edinburgh, UK.
¹² Department of Human Anatomy and Embryology, School of Medicine, University of Granada, Granada, Spain.
¹³ Centre for Genomics and Oncological Research (GENYO), Avenida de la Ilustración 114, 18016, Granada, Spain. davidlandeira@ugr.es.
¹⁴ Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, University of Granada, Granada, Spain. davidlandeira@ugr.es.
¹⁵ Instituto de Investigación Biosanitaria ibs.GRANADA, Granada, Spain. davidlandeira@ugr.es.

^# Contributed equally.

PMID: 35680984
DOI: 10.1038/s41388-022-02375-x

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

Amador Gallardo et al. Oncogene. 2022 Jul.

. 2022 Jul;41(28):3611-3624.

doi: 10.1038/s41388-022-02375-x. Epub 2022 Jun 9.

Authors

Affiliations

¹ Centre for Genomics and Oncological Research (GENYO), Avenida de la Ilustración 114, 18016, Granada, Spain.
² Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, University of Granada, Granada, Spain.
³ Instituto de Investigación Biosanitaria ibs.GRANADA, Granada, Spain.
⁴ Department of Biochemistry and Molecular Biology I, Faculty of Sciences, University of Granada, Granada, Spain.
⁵ Department of Statistics, Faculty of Sciences, University of Granada, Granada, Spain.
⁶ Data Science for Health Research Unit, Fondazione Bruno Kessler, Trento, Italy.
⁷ UGC de Oncología Médica, Complejo Hospitalario de Jaen, 23007, Jaen, Spain.
⁸ Department of Applied Physics, Faculty of Science, University of Granada, 18071, Granada, Spain.
⁹ Biopathology and Regenerative Medicine Institute (IBIMER), Centre for Biomedical Research (CIBM), University of Granada, 18016, Granada, Spain.
¹⁰ Excellence Research Unit Modelling Nature (MNat), University of Granada, 18016, Granada, Spain.
¹¹ Cancer Research UK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, EH4 2XU, Edinburgh, UK.
¹² Department of Human Anatomy and Embryology, School of Medicine, University of Granada, Granada, Spain.
¹³ Centre for Genomics and Oncological Research (GENYO), Avenida de la Ilustración 114, 18016, Granada, Spain. davidlandeira@ugr.es.
¹⁴ Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, University of Granada, Granada, Spain. davidlandeira@ugr.es.
¹⁵ Instituto de Investigación Biosanitaria ibs.GRANADA, Granada, Spain. davidlandeira@ugr.es.

^# Contributed equally.

PMID: 35680984
DOI: 10.1038/s41388-022-02375-x

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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References

1. Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Investig. 2009;119:1420–8. https://doi.org/10.1172/jci39104 - DOI - PubMed - PMC
1. Thiery JP, Acloque H, Huang RY, Nieto MA. Epithelial-mesenchymal transitions in development and disease. Cell. 2009;139:871–90. https://doi.org/10.1016/j.cell.2009.11.007 - DOI - PubMed
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[1] Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Investig. 2009;119:1420–8. https://doi.org/10.1172/jci39104 - DOI - PubMed - PMC

[2] Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Investig. 2009;119:1420–8. https://doi.org/10.1172/jci39104 - DOI - PubMed - PMC

[3] Thiery JP, Acloque H, Huang RY, Nieto MA. Epithelial-mesenchymal transitions in development and disease. Cell. 2009;139:871–90. https://doi.org/10.1016/j.cell.2009.11.007 - DOI - PubMed

[4] Thiery JP, Acloque H, Huang RY, Nieto MA. Epithelial-mesenchymal transitions in development and disease. Cell. 2009;139:871–90. https://doi.org/10.1016/j.cell.2009.11.007 - DOI - PubMed

[5] Dongre A, Weinberg RA. New insights into the mechanisms of epithelial-mesenchymal transition and implications for cancer. Nat Rev Mol cell Biol. 2019;20:69–84. https://doi.org/10.1038/s41580-018-0080-4 - DOI - PubMed

[6] Dongre A, Weinberg RA. New insights into the mechanisms of epithelial-mesenchymal transition and implications for cancer. Nat Rev Mol cell Biol. 2019;20:69–84. https://doi.org/10.1038/s41580-018-0080-4 - DOI - PubMed

[7] Tam WL, Weinberg RA. The epigenetics of epithelial-mesenchymal plasticity in cancer. Nat Med. 2013;19:1438–49. https://doi.org/10.1038/nm.3336 - DOI - PubMed - PMC

[8] Tam WL, Weinberg RA. The epigenetics of epithelial-mesenchymal plasticity in cancer. Nat Med. 2013;19:1438–49. https://doi.org/10.1038/nm.3336 - DOI - PubMed - PMC

[9] Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol cell Biol. 2014;15:178–96. https://doi.org/10.1038/nrm3758 - DOI - PubMed - PMC

[10] Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol cell Biol. 2014;15:178–96. https://doi.org/10.1038/nrm3758 - DOI - PubMed - PMC

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

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