Mutant Lef1 controls Gata6 in sebaceous gland development and cancer

TY - JOUR

T1 - Mutant Lef1 controls Gata6 in sebaceous gland development and cancer

AU - Oulès, Bénédicte

AU - Rognoni, Emanuel

AU - Hoste, Esther

AU - Goss, Georgina

AU - Fiehler, Ryan

AU - Natsuga, Ken

AU - Quist, Sven

AU - Mentink, Remco

AU - Donati, Giacomo

AU - Watt, Fiona M

N1 - © 2019 The Authors. Published under the terms of the CC BY 4.0 license.

PY - 2019/5/2

Y1 - 2019/5/2

N2 - 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.

AB - 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.

KW - DNA mismatch repair

KW - Gata6

KW - Lef1

KW - sebaceous gland

KW - sebaceous tumors

UR - http://www.scopus.com/inward/record.url?scp=85064825572&partnerID=8YFLogxK

U2 - 10.15252/embj.2018100526

DO - 10.15252/embj.2018100526

M3 - Article

C2 - 30886049

SN - 0261-4189

VL - 38

JO - The EMBO journal

JF - The EMBO journal

IS - 9

M1 - e100526

ER -