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Mutant Lef1 controls Gata6 in sebaceous gland development and cancer

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Bénédicte Oulès, Emanuel Rognoni, Esther Hoste, Georgina Goss, Ryan Fiehler, Ken Natsuga, Sven Quist, Remco Mentink, Giacomo Donati, Fiona M Watt

Original languageEnglish
Article numbere100526
JournalThe EMBO journal
Volume38
Issue number9
Early online date18 Mar 2019
DOIs
Accepted/In press19 Feb 2019
E-pub ahead of print18 Mar 2019
Published2 May 2019

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© 2019 The Authors. Published under the terms of the CC BY 4.0 license.

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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.

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