Title: LSD1 Inhibition Promotes Epithelial Differentiation through Derepression of Fate-Determining Transcription Factors.
Authors: Egolf, Shaun; Aubert, Yann; Doepner, Miriam; Anderson, Amy; Maldonado-Lopez, Alexandra; Pacella, Gina; Lee, Jessica; Ko, Eun Kyung; Zou, Jonathan; Lan, Yemin; Simpson, Cory L; Ridky, Todd; Capell, Brian C
Published In Cell Rep, (2019 08 20)
Abstract: Self-renewing somatic tissues depend upon the proper balance of chromatin-modifying enzymes to coordinate progenitor cell maintenance and differentiation, disruption of which can promote carcinogenesis. As a result, drugs targeting the epigenome hold significant therapeutic potential. The histone demethylase, LSD1 (KDM1A), is overexpressed in numerous cancers, including epithelial cancers; however, its role in the skin is virtually unknown. Here we show that LSD1 directly represses master epithelial transcription factors that promote differentiation. LSD1 inhibitors block both LSD1 binding to chromatin and its catalytic activity, driving significant increases in H3K4 methylation and gene transcription of these fate-determining transcription factors. This leads to both premature epidermal differentiation and the repression of squamous cell carcinoma. Together these data highlight both LSD1's role in maintaining the epidermal progenitor state and the potential of LSD1 inhibitors for the treatment of keratinocyte cancers, which collectively outnumber all other cancers combined.
PubMed ID: 31433976
MeSH Terms: 3T3 Cells; Adult; Animals; Binding Sites; Carcinoma, Squamous Cell/pathology; Cell Differentiation*/genetics; Cell Line, Tumor; Cell Lineage*/genetics; Epidermis/metabolism; Epithelial Cells/cytology*; Epithelial Cells/metabolism; Gene Expression Regulation; Genome, Human; Histone Demethylases/antagonists & inhibitors*; Histone Demethylases/metabolism; Histones/metabolism; Humans; Lysine/metabolism; Methylation; Mice; Protein Binding; Snail Family Transcription Factors/metabolism; Transcription Factors/metabolism*; Transcription, Genetic