Mutant Lef1 controls Gata6 in sebaceous gland development and cancer.
Bénédicte OulèsEmanuel RognoniEsther HosteGeorgina GossRyan FiehlerKen NatsugaSven QuistRemco MentinkGiacomo DonatiFiona M WattPublished in: The EMBO journal (2019)
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.
Keyphrases
- transcription factor
- endothelial cells
- genome wide identification
- dna binding
- papillary thyroid
- induced pluripotent stem cells
- genome wide
- high grade
- poor prognosis
- stem cells
- pluripotent stem cells
- cell proliferation
- wild type
- circulating tumor
- skeletal muscle
- atrial fibrillation
- epithelial mesenchymal transition
- long non coding rna
- mesenchymal stem cells
- ultrasound guided
- heat shock
- binding protein
- radiofrequency ablation