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Describing a Transcription Factor Dependent Regulation of the MicroRNA Transcriptome
Published on: June 15, 2016
LSD1 Inhibition Promotes Epithelial Differentiation through Derepression of Fate-Determining Transcription Factors
Shaun Egolf1, Yann Aubert1, Miriam Doepner2
1Penn Epigenetics Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
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.
Insights
Lysine-specific demethylase 1 (LSD1) inhibitors promote epidermal differentiation and suppress squamous cell carcinoma by reactivating key transcription factors. These findings suggest LSD1 inhibitors are a promising therapeutic strategy for keratinocyte cancers.
Area of Science:
- Epigenetics
- Cancer Biology
- Dermatology
Background:
- Somatic tissue renewal relies on chromatin modifiers for progenitor cell balance.
- Epigenetic drugs offer therapeutic potential for cancer treatment.
- The histone demethylase LSD1 (KDM1A) is implicated in various cancers but its role in skin is unclear.
Purpose of the Study:
- To investigate the role of LSD1 in skin homeostasis and keratinocyte differentiation.
- To evaluate the therapeutic potential of LSD1 inhibitors in skin cancers.
Main Methods:
- Assessed LSD1's direct repression of epithelial transcription factors.
- Utilized LSD1 inhibitors to block chromatin binding and catalytic activity.
- Measured changes in H3K4 methylation and gene transcription.
Main Results:
- LSD1 directly represses key transcription factors essential for epidermal differentiation.
- LSD1 inhibition increased H3K4 methylation and transcription of differentiation factors.
- This led to premature epidermal differentiation and suppressed squamous cell carcinoma.
Conclusions:
- LSD1 maintains the epidermal progenitor state by repressing differentiation.
- LSD1 inhibitors show potential for treating keratinocyte cancers, which are highly prevalent.
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