Tri-methylation of H3K79 is decreased in TGF-β1-induced epithelial-to-mesenchymal transition in lung cancer

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Abstract

Background

The epithelial-to-mesenchymal transition (EMT) enables epithelial cancer cells to acquire mesenchymal features and contributes to metastasis and resistance to treatment. This process involves epigenetic reprogramming for gene expression. We explored global histone modifications during TGF-β1-induced EMT in two non-small cell lung cancer (NSCLC) cell lines and tested different epigenetic treatment to modulate or partially reverse EMT.

Results

Loss of classical epithelial markers and gain of mesenchymal markers were verified in A549 and H358 cell lines during TGF-β1-induced EMT. In addition, we noticed increased expression of the axonal guidance protein semaphorin 3C (SEMA3C) and PD-L1 (programmed death-ligand 1) involved in the inhibition of the immune system, suggesting that both SEMA3C and PD-L1 could be the new markers of TGF-β1-induced EMT. H3K79me3 and H2BK120me1 were decreased in A549 and H358 cell lines after a 48-h TGF-β1 treatment, as well as H2BK120ac in A549 cells. However, decreased H3K79me3 was not associated with expression of the histone methyltransferase DOT1L. Furthermore, H3K79me3 was decreased in tumors compared in normal tissues and not associated with cell proliferation. Associations of histone deacetylase inhibitor (SAHA) with DOT1L inhibitors (EPZ5676 or SGC0946) or BET bromodomain inhibitor (PFI-1) were efficient to partially reverse TGF-β1 effects by decreasing expression of PD-L1, SEMA3C, and its receptor neuropilin-2 (NRP2) and by increasing epithelial markers such as E-cadherin.

Conclusion

Histone methylation was modified during EMT, and combination of epigenetic compounds with conventional or targeted chemotherapy might contribute to reduce metastasis and to enhance clinical responses.

Electronic supplementary material

The online version of this article (doi:10.1186/s13148-017-0380-0) contains supplementary material, which is available to authorized users.

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Most cited references 41

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Epithelial-mesenchymal transitions in development and disease.

Jean Paul Thiery, Hervé Acloque, Ruby Y J Huang … (2009)

The epithelial to mesenchymal transition (EMT) plays crucial roles in the formation of the body plan and in the differentiation of multiple tissues and organs. EMT also contributes to tissue repair, but it can adversely cause organ fibrosis and promote carcinoma progression through a variety of mechanisms. EMT endows cells with migratory and invasive properties, induces stem cell properties, prevents apoptosis and senescence, and contributes to immunosuppression. Thus, the mesenchymal state is associated with the capacity of cells to migrate to distant organs and maintain stemness, allowing their subsequent differentiation into multiple cell types during development and the initiation of metastasis.

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Programmed death ligand-1 expression in non-small cell lung cancer.

Vamsidhar Velcheti, Kurt Schalper, Daniel E Carvajal … (2014)

Recent strategies targeting the interaction of the programmed cell death ligand-1 (PD-L1, B7-H1, CD274) with its receptor, PD-1, resulted in promising activity in early phase clinical trials. In this study, we used various antibodies and in situ mRNA hybridization to measure PD-L1 in non-small cell lung cancer (NSCLC) using a quantitative fluorescence (QIF) approach to determine the frequency of expression and prognostic value in two independent populations. A control tissue microarray (TMA) was constructed using PD-L1-transfected cells, normal human placenta and known PD-L1-positive NSCLC cases. Only one of four antibodies against PD-L1 (5H1) validated for specificity on this TMA. In situ PD-L1 mRNA using the RNAscope method was similarly validated. Two cohorts of NSCLC cases in TMAs including 340 cases from hospitals in Greece and 204 cases from Yale University were assessed. Tumors showed PD-L1 protein expression in 36% (Greek) and 25% (Yale) of the cases. PD-L1 expression was significantly associated with tumor-infiltrating lymphocytes in both cohorts. Patients with PD-L1 (both protein and mRNA) expression above the detection threshold showed statistically significant better outcome in both series (log-rank P=0.036 and P=0.027). Multivariate analysis showed that PD-L1 expression was significantly associated with better outcome independent of histology. Measurement of PD-L1 requires specific conditions and some commercial antibodies show lack of specificity. Expression of PD-L1 protein or mRNA is associated with better outcome. Further studies are required to determine the value of this marker in prognosis and prediction of response to treatments targeting this pathway.

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LncRNA-Dependent Mechanisms of Androgen Receptor-regulated Gene Activation Programs

Liuqing Yang, Chunru Lin, Chunyu Jin … (2013)

While recent studies indicated roles of long non-coding RNAs (lncRNAs) in physiologic aspects of cell-type determination and tissue homeostasis 1 yet their potential involvement in regulated gene transcription programs remain rather poorly understood. Androgen receptor (AR) regulates a large repertoire of genes central to the identity and behavior of prostate cancer cells 2 , and functions in a ligand-independent fashion in many prostate cancers when they become hormone refractory after initial androgen deprivation therapy 3 . Here, we report that two lncRNAs highly overexpressed in aggressive prostate cancer, PRNCR1 and PCGEM1, bind successively to the AR and strongly enhance both ligand-dependent and ligand-independent AR-mediated gene activation programs and proliferation in prostate cancer cells. Binding of PRNCR1 to the C-terminally acetylated AR on enhancers and its association with DOT1L appear to be required for recruitment of the second lncRNA, PCGEM1, to the DOT1L-mediated methylated AR N-terminus. Unexpectedly, recognition of specific protein marks by PCGEM1-recruited Pygopus2 PHD domain proves to enhance selective looping of AR-bound enhancers to target gene promoters in these cells. In “resistant” prostate cancer cells, these overexpressed lncRNAs can interact with, and are required for, the robust activation of both truncated and full length AR, causing ligand-independent activation of the AR transcriptional program and cell proliferation. Conditionally-expressed short hairpin RNA (shRNA) targeting of these lncRNAs in castration-resistant prostate cancer (CRPC) cell lines strongly suppressed tumor xenograft growth in vivo. Together, these results suggest that these overexpressed lncRNAs can potentially serve as a required component of castration-resistance in prostatic tumors.

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Author and article information

Contributors

Emilie Evanno: emilie.evanno@sfr.fr

Julie Godet: julie.godet@chu-poitiers.fr

Nathalie Piccirilli: Nathalie.PICCIRILLI@chu-poitiers.fr

Joëlle Guilhot: Joelle.GUILHOT-GAUDEFFROY@chu-poitiers.fr

Serge Milin: serge.milin@chu-poitiers.fr

Jean Marc Gombert: Jean-Marc.GOMBERT@chu-poitiers.fr

Benoit Fouchaq: benoitfouchaq@eurofins.com

Joëlle Roche:

ORCID: http://orcid.org/0000-0002-4605-1749

(33) 5 49 45 35 50 , joelle.roche@univ-poitiers.fr

Journal

Journal ID (nlm-ta): Clin Epigenetics

Journal ID (iso-abbrev): Clin Epigenetics

Title: Clinical Epigenetics

Publisher: BioMed Central (London )

ISSN (Print): 1868-7075

ISSN (Electronic): 1868-7083

Publication date (Electronic): 8 August 2017

Publication date PMC-release: 8 August 2017

Publication date Collection: 2017

Volume: 9

Electronic Location Identifier: 80

Affiliations

[1 ]Eurofins Cerep SA, Le Bois l’Evêque, F-86600 Celle L’Evescault, France

[2 ]ISNI 0000 0001 2160 6368, GRID grid.11166.31, , Université de Poitiers, Laboratoire LNEC, ; F-86022 Poitiers, France

[3 ]ISNI 0000 0000 9336 4276, GRID grid.411162.1, , CHU de Poitiers, Service d’Anatomie et de Cytologie Pathologiques, ; F-86021 Poitiers, France

[4 ]ISNI 0000 0000 9336 4276, GRID grid.411162.1, , INSERM U1082, CHU de Poitiers, ; F-86021 Poitiers, France

[5 ]ISNI 0000 0000 9336 4276, GRID grid.411162.1, , INSERM CIC 0802, CHU de Poitiers, ; F-86021 Poitiers, France

[6 ]ISNI 0000 0000 9336 4276, GRID grid.411162.1, , Service Immunologie, CHU de Poitiers, ; F-86021 Poitiers, France

[7 ]ISNI 0000 0001 2160 6368, GRID grid.11166.31, Laboratoire Ecologie et Biologie des Interactions (EBI), , Université de Poitiers, UMR-CNRS 7267, ; F-86073 Poitiers, France

Author information

Joëlle Roche http://orcid.org/0000-0002-4605-1749

Article

Publisher ID: 380

DOI: 10.1186/s13148-017-0380-0

PMC ID: 5549304

PubMed ID: 28804523

SO-VID: 10d96642-40cf-4472-8c88-4abb54f5cf36

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 21 October 2016

Date accepted : 31 July 2017

Funding

Funded by: FEDER

Award ID: FEDER 38345-2013

Award Recipient : Benoit Fouchaq

Funded by: Région Poitou Charentes

Award ID: Région Poitou Charentes

Custom metadata

ScienceOpen disciplines: Genetics

Keywords: lung cancer,nsclc,emt,h3k79me3,dot1l,pd-l1,sema3c,nrp2,epigenetic treatment

Data availability:

ScienceOpen disciplines: Genetics

Keywords: lung cancer, nsclc, emt, h3k79me3, dot1l, pd-l1, sema3c, nrp2, epigenetic treatment

Tri-methylation of H3K79 is decreased in TGF-β1-induced epithelial-to-mesenchymal transition in lung cancer

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Abstract

Background

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Evolutionary Cell Biology

Most cited references 41

Epithelial-mesenchymal transitions in development and disease.

Programmed death ligand-1 expression in non-small cell lung cancer.

LncRNA-Dependent Mechanisms of Androgen Receptor-regulated Gene Activation Programs

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