Mutant Lef1 controls Gata6 in sebaceous gland development and cancer

EMBO J. 2019 May 2;38(9):e100526. doi: 10.15252/embj.2018100526. Epub 2019 Mar 18.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation
  • DNA Damage
  • Female
  • GATA6 Transcription Factor / metabolism*
  • Hair Follicle / metabolism
  • Hair Follicle / pathology
  • Humans
  • Lymphoid Enhancer-Binding Factor 1 / genetics
  • Lymphoid Enhancer-Binding Factor 1 / metabolism*
  • Lymphoid Enhancer-Binding Factor 1 / physiology*
  • Male
  • Mice
  • Mice, Knockout
  • MutL Protein Homolog 1 / genetics
  • MutL Protein Homolog 1 / metabolism
  • MutS Homolog 2 Protein / genetics
  • MutS Homolog 2 Protein / metabolism
  • Mutation
  • Sebaceous Gland Neoplasms / genetics
  • Sebaceous Gland Neoplasms / metabolism
  • Sebaceous Gland Neoplasms / pathology*
  • Skin Neoplasms / genetics
  • Skin Neoplasms / metabolism
  • Skin Neoplasms / pathology*
  • Stem Cells / metabolism
  • Stem Cells / pathology*
  • beta Catenin / genetics
  • beta Catenin / metabolism


  • GATA6 Transcription Factor
  • LEF1 protein, human
  • Lef1 protein, mouse
  • Lymphoid Enhancer-Binding Factor 1
  • beta Catenin
  • MSH2 protein, human
  • Msh2 protein, mouse
  • MutL Protein Homolog 1
  • MutS Homolog 2 Protein