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LSD1 Inhibition Promotes Epithelial Differentiation through Derepression of Fate-Determining Transcription Factors

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 de...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6719800/
https://www.ncbi.nlm.nih.gov/pubmed/31433976
http://dx.doi.org/10.1016/j.celrep.2019.07.058
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author 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.
author_facet 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.
author_sort Egolf, Shaun
collection PubMed
description 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.
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spelling pubmed-67198002019-09-03 LSD1 Inhibition Promotes Epithelial Differentiation through Derepression of Fate-Determining Transcription Factors 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. Cell Rep Article 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. 2019-08-20 /pmc/articles/PMC6719800/ /pubmed/31433976 http://dx.doi.org/10.1016/j.celrep.2019.07.058 Text en This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
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.
LSD1 Inhibition Promotes Epithelial Differentiation through Derepression of Fate-Determining Transcription Factors
title LSD1 Inhibition Promotes Epithelial Differentiation through Derepression of Fate-Determining Transcription Factors
title_full LSD1 Inhibition Promotes Epithelial Differentiation through Derepression of Fate-Determining Transcription Factors
title_fullStr LSD1 Inhibition Promotes Epithelial Differentiation through Derepression of Fate-Determining Transcription Factors
title_full_unstemmed LSD1 Inhibition Promotes Epithelial Differentiation through Derepression of Fate-Determining Transcription Factors
title_short LSD1 Inhibition Promotes Epithelial Differentiation through Derepression of Fate-Determining Transcription Factors
title_sort lsd1 inhibition promotes epithelial differentiation through derepression of fate-determining transcription factors
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6719800/
https://www.ncbi.nlm.nih.gov/pubmed/31433976
http://dx.doi.org/10.1016/j.celrep.2019.07.058
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