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The EGF receptor ligand amphiregulin controls cell division via FoxM1

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Abstract

Epidermal growth factor receptor (EGFR) is central to epithelial cell physiology, and deregulated EGFR signaling has an important role in a variety of human carcinomas. Here we show that silencing of the EGF-related factor amphiregulin (AREG) markedly inhibits the expansion of human keratinocytes through mitotic failure and accumulation of cells with ⩾4n DNA content. RNA-sequencing-based transcriptome analysis revealed that tetracycline-mediated AREG silencing significantly altered the expression of 2331 genes, 623 of which were not normalized by treatment with EGF. Interestingly, genes irreversibly upregulated by suppression of AREG overlapped with genes involved in keratinocyte differentiation. Moreover, a significant proportion of the irreversibly downregulated genes featured upstream binding sites recognized by forkhead box protein M1 (FoxM1), a key transcription factor in the control of mitosis that is widely dysregulated in cancer. The downregulation of FoxM1 and its target genes preceded mitotic arrest. Constitutive expression of FoxM1 in AREG knockdown cells normalized cell proliferation, reduced the number of cells with ⩾4n DNA content and rescued expression of FoxM1 target genes. These results demonstrate that AREG controls G2/M progression and cytokinesis in keratinocytes via activation of a FoxM1-dependent transcriptional program, suggesting new avenues for treatment of epithelial cancer.

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Accession codes

Accessions

Gene Expression Omnibus

Abbreviations

AREG:

amphiregulin

CFSE:

carboxyfluorescein succinimidyl ester

DAPI:

4‘,6-diamidino-2-phenylindole

DEG:

differentially expressed gene

EGF:

epidermal growth factor

EGFP:

enhanced green fluorescent protein

EGFR:

EGF receptor

ERK:

extracellular signal-regulated kinase

FoxM1:

forkhead box protein M1

GF:

growth factor

HB-EGF:

heparin-binding EGF-like growth factor

QRT–PCR:

quantitative real-time–polymerase chain reaction

Tet:

tetracycline

TGF-α:

transforming growth factor-α

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Acknowledgements

We thank Mahdu Prasad for assistance with RNA-seq assays and Dr James Rheinwald (Harvard Medical School, Boston, MA) for providing the N/TERT-2G keratinocyte cell line. This work was in part supported by the National Institute for Arthritis, Musculoskeletal and Skin Disease (NIAMS), National Institutes of Health (NIH award K01 AR050462 and R03 AR049420 to SWS, K01 AR064765 to AJ and R01 AR052889 to JTE) and Instituto de Salud Carlos III (Spain, ISCIII-FIS/FEDER, PI11/02070, to AG). AJ is supported by a Babcock Foundation Endowment. JTE is supported by the Ann Arbor Veterans Affairs Hospital.

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Authors and Affiliations

  1. Department of Dermatology, University of Michigan, Ann Arbor, MI, USA

    S W Stoll, P E Stuart, W R Swindell, S Lambert, A Johnston, R P Nair & J T Elder

  2. Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA

    L C Tsoi

  3. Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA

    B Li

  4. Cell Cycle, Stem Cell Fate and Cancer Laboratory, Fundación Instituto de Investigación Marqués de Valdecilla (IDIVAL), Santander, Spain,

    A Gandarillas

  5. Ann Arbor Veterans Affairs Health System, Ann Arbor, MI, USA

    J T Elder

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  1. S W Stoll
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Stoll, S., Stuart, P., Swindell, W. et al. The EGF receptor ligand amphiregulin controls cell division via FoxM1. Oncogene 35, 2075–2086 (2016). https://doi.org/10.1038/onc.2015.269

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