LSD1 Inhibition Promotes Epithelial Differentiation through Derepression of Fate-Determining Transcription Factors
| Autor: | Miriam Doepner, Jessica T. Lee, Eunkyung Ko, Yemin Lan, Todd W. Ridky, Gina Pacella, Alexandra Maldonado-Lopez, Brian C. Capell, Yann Aubert, Shaun Egolf, Jonathan Zou, A. Anderson, Cory L. Simpson |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Adult animal structures Transcription Genetic Methylation General Biochemistry Genetics and Molecular Biology Article Histones 03 medical and health sciences Mice 0302 clinical medicine Cell Line Tumor Animals Humans Cell Lineage Epigenetics Progenitor cell Transcription factor lcsh:QH301-705.5 Histone Demethylases Binding Sites biology Genome Human Lysine KDM1A Cell Differentiation Epithelial Cells Epigenome 3T3 Cells 3. Good health Chromatin Cell biology 030104 developmental biology Histone lcsh:Biology (General) Gene Expression Regulation biology.protein Carcinoma Squamous Cell Demethylase Snail Family Transcription Factors Epidermis 030217 neurology & neurosurgery Protein Binding Transcription Factors |
| Zdroj: | Cell reports Cell Reports, Vol 28, Iss 8, Pp 1981-1992.e7 (2019) |
| ISSN: | 2211-1247 |
| Popis: | SUMMARY 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. Graphical Abstract In Brief Egolf et al. demonstrate that inhibition of the epigenetic regulator and histone demethylase, LSD1, promotes activation of the epidermal differentiation transcriptional program and, in turn, represses the invasion of cutaneous squamous cell carcinoma, one of the most common of all human cancers. |
| Databáze: | OpenAIRE |
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