Mutant Lef1 controls Gata6 in sebaceous gland development and cancer

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.

Multiple roles and regulatory mechanisms of the transcription factor GATA6 in human cancers

“…In addition, according to a recent study on cutaneous T‐cell lymphoma (CTCL), GATA6 directly up‐regulates CD137L expression and promotes tumor growth . In a study of animal models of sebaceous gland (SG) tumors, Gata6 was found to control sebaceous gland development and cancer . Because GATA6 can be differentially expressed in prostate cancer, GATA6 can be used not only as a candidate biomarker for prostate cancer, but also as a potential therapeutic target .…”

“…101 In a study of animal models of sebaceous gland (SG) tumors, Gata6 was found to control sebaceous gland development and cancer. 102 Because GATA6 can be differentially expressed in prostate cancer, GATA6 can be used not only as a candidate biomarker for prostate cancer, but also as a potential therapeutic target. 103 The transcription factor GATA6 is also associated with the occurrence of adrenocortical tumors.…”

Tracing the cellular dynamics of sebaceous gland development in normal and perturbed states

“…Multiple models have been proposed for SG maintenance, including models where specialised cells located either within or outside the gland are the source of replenishment [5][6][7][8][9] . Moreover, developmental studies suggest that SGs are derived from more than 1 Lrig1 expressing cells [10][11][12] . Yet, a general consensus is still lacking for how the SG forms, how it is subsequently maintained and how oncogene activation affects cell behaviour.…”

Development and Maintenance of Epidermal Stem Cells in Skin Adnexa

“…A subset of Lrig1 + cells also expresses the transcription factor Gata6 which regulates sebaceous lineage specification. Gata6 + cells appear in the HF infundibulum, junctional zone, upper SG and its duct portion [ 21 , 22 ]. Other SC populations, expressing LGR6, MTS24/PLET1 and K15 and occupying the isthmus, junctional zone and bulge, can participate in the generation of SG progeny [ 23 , 24 , 25 ].…”

“…Lrig1 and Lrg6 expression appears in the basal layer that is responsible for SG homeostasis. Gata6 lo cells coexpress Lrig1 and Lrg6; postnatally, these cells are localized in the junctional zone, the upper part of SGs and sebaceous duct [ 21 , 22 ]. SGSCs are not dependent on Lgr6 + SCs from adjacent compartments comprising HFs and IFE.…”