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The Grainyhead transcription factor Grhl3/Get1 suppresses miR-21 expression and tumorigenesis in skin: modulation of the miR-21 target MSH2 by RNA-binding protein DND1

Oncogene volume 32, pages 1497–1507 (2013)Cite this article

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Abstract

Epidermal differentiation and stratification, crucial for barrier formation, are regulated by a complex interplay of transcription factors, including the evolutionarily conserved Grainyhead-like 3 (Grhl3/Get1); Grhl3-deleted mice exhibit impaired epidermal differentiation and decreased expression of multiple differentiation genes. To test whether Grhl3 regulates epidermal genes indirectly by controlling the expression of specific microRNAs (miRs), we performed miR profiling and identified 11 miRs that are differentially regulated in Grhl3−/− skin, one of which is miR-21, previously shown to be upregulated in diseased skin, including in psoriasis and squamous cell skin cancer. We found that miR-21 is normally expressed in the post-mitotic suprabasal layers of the epidermis, overlapping with Grhl3. The miR-21 promoter is bound and repressed by Grhl3 indicating that these two factors are involved in a regulatory loop maintaining homeostasis in the epidermis. Although miR-21 overexpression in normal keratinocytes had mild effects on the expression of several known miR-21 targets, an enhanced downregulation of the miR-21 tumor-related targets, including MSH2, was observed in Ras-transformed keratinocytes. The increased sensitivity of transformed keratinocytes to miR-21’s effects occurs in part through downregulation of the RNA-binding protein DND1 during the transformation process. Additionally, we observed increased tumorigenesis in mice subcutaneously injected with transformed keratinocytes lacking Grhl3. These findings indicate that decreased Grhl3 expression contributes to tumor progression and upregulation of the oncomir miR-21 in squamous cell carcinoma of the skin.

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Acknowledgements

We thank Stuart Yuspa and Andrew Ryscavage for the gift of mouse papilloma and carcinoma sample and the Ras virus. We also thank Reuven Agami for HA-DND1 expression plasmid. This work was supported by grants from the NIH (AR44882) and the Irving Weinstein Foundation (to BA); the California Tobacco Related Disease Research Program (17DT-0192 to AB); the NIH training program in Systems Biology of Development (T32-HD60555 to WG); the National Library of Medicine training grant (LM07443 to EG).

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  1. A Bhandari and W Gordon: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medicine, Department of Biological Chemistry, University of California, Irvine, Irvine, CA, USA

    A Bhandari, W Gordon, D Dizon, A S Hopkin, Z Yu & B Andersen

  2. Center for Complex Biological Systems, University of California, Irvine, Irvine, CA, USA

    W Gordon & B Andersen

  3. Department of Development and Cell Biology, University of California, Irvine, Irvine, CA, USA

    E Gordon

  4. Institute for Genomics and Bioinformatics, University of California, Irvine, Irvine, CA, USA

    E Gordon

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  1. A Bhandari
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Bhandari, A., Gordon, W., Dizon, D. et al. The Grainyhead transcription factor Grhl3/Get1 suppresses miR-21 expression and tumorigenesis in skin: modulation of the miR-21 target MSH2 by RNA-binding protein DND1. Oncogene 32, 1497–1507 (2013). https://doi.org/10.1038/onc.2012.168

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