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EMBO J. 2019 Mar 18. pii: e100526. doi: 10.15252/embj.2018100526. [Epub ahead of print]

Mutant Lef1 controls Gata6 in sebaceous gland development and cancer.

Author information

1
Centre for Stem Cells and Regenerative Medicine, King's College London, London, UK.
2
Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
3
Unit for Cellular and Molecular Pathophysiology, VIB Center for Inflammation Research, Ghent, Belgium.
4
Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
5
F-star Biotechnology Limited, Cambridge, UK.
6
Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
7
Clinic for Dermatology and Venereology, Otto-von-Guericke-University, Magdeburg, Germany.
8
Bejo, Warmenhuizen, The Netherlands.
9
Department of Life Sciences and Systems Biology, Molecular Biotechnology Center, University of Turin, Turin, Italy.
10
Centre for Stem Cells and Regenerative Medicine, King's College London, London, UK fiona.watt@kcl.ac.uk.

Abstract

Mutations in Lef1 occur in human and mouse sebaceous gland (SG) tumors, but their contribution to carcinogenesis remains unclear. Since Gata6 controls lineage identity in SG, we investigated the link between these two transcription factors. Here, we show that Gata6 is a β-catenin-independent transcriptional target of mutant Lef1. During epidermal development, Gata6 is expressed in a subset of Sox9-positive Lef1-negative hair follicle progenitors that give rise to the upper SG Overexpression of Gata6 by in utero lentiviral injection is sufficient to induce ectopic sebaceous gland elements. In mice overexpressing mutant Lef1, Gata6 ablation increases the total number of skin tumors yet decreases the proportion of SG tumors. The increased tumor burden correlates with impaired DNA mismatch repair and decreased expression of Mlh1 and Msh2 genes, defects frequently observed in human sebaceous neoplasia. Gata6 specifically marks human SG tumors and also defines tumors with elements of sebaceous differentiation, including a subset of basal cell carcinomas. Our findings reveal that Gata6 controls sebaceous gland development and cancer.

KEYWORDS:

DNA mismatch repair; Gata6; Lef1; sebaceous gland; sebaceous tumors

PMID:
30886049
DOI:
10.15252/embj.2018100526
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