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

Egolf, Shaun; Aubert, Yann; Doepner, Miriam; Anderson, A.; Maldonado-Lopez, Alexandra; Pacella, G; Lee, Jessica; Ko, Eun Kyung; Zou, Jonathan; Lan, Yemin; Simpson, Cory L.; Ridky, Todd W.; Capell, Brian C.

doi:10.1016/j.celrep.2019.07.058

Cited by 59 publications

(57 citation statements)

References 75 publications

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“…Here, we find that LSD1 is required for postnatal intestinal epithelial maturation. The role we find for LSD1 in suppressing fetal/neonatal genes is near opposite of what recently was found in skin ( 39 ). In skin epithelium, inhibition of LSD1 leads to the increase of fate-determining transcription factors and subsequent differentiation, and this enhanced differentiation led to inhibition of skin cancer progression ( 39 ).…”

Section: Discussioncontrasting

confidence: 99%

LSD1 represses a neonatal/reparative gene program in adult intestinal epithelium

et al. 2020

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Intestinal epithelial homeostasis is maintained by adult intestinal stem cells, which, alongside Paneth cells, appear after birth in the neonatal period. We aimed to identify regulators of neonatal intestinal epithelial development by testing a small library of epigenetic modifier inhibitors in Paneth cell–skewed organoid cultures. We found that lysine-specific demethylase 1A (Kdm1a/Lsd1) is absolutely required for Paneth cell differentiation. Lsd1-deficient crypts, devoid of Paneth cells, are still able to form organoids without a requirement of exogenous or endogenous Wnt. Mechanistically, we find that LSD1 enzymatically represses genes that are normally expressed only in fetal and neonatal epithelium. This gene profile is similar to what is seen in repairing epithelium, and we find that Lsd1-deficient epithelium has superior regenerative capacities after irradiation injury. In summary, we found an important regulator of neonatal intestinal development and identified a druggable target to reprogram intestinal epithelium toward a reparative state.

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Section: Discussioncontrasting

confidence: 99%

LSD1 represses a neonatal/reparative gene program in adult intestinal epithelium

et al. 2020

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“…KDM1A is overexpressed in numerous epithelial cancers and promotes proliferation, migration and invasion. Egolf et al [65] reported that its downstream targets were involved in epidermal differentiation and cornification processes. Kong et al [66] indicated that treatment with KDM1A inhibitor (2-PCPA) reduced tumour NSCLC cell proliferation and migration.…”

Section: Discussionmentioning

confidence: 99%

Molecular Signature of Subtypes of Non-Small-Cell Lung Cancer by Large-Scale Transcriptional Profiling: Identification of Key Modules and Genes by Weighted Gene Co-Expression Network Analysis (WGCNA)

Niemira

Collin

Szałkowska

et al. 2019

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Non-small-cell lung cancer (NSCLC) represents a heterogeneous group of malignancies consisting essentially of adenocarcinoma (ADC) and squamous cell carcinoma (SCC). Although the diagnosis and treatment of ADC and SCC have been greatly improved in recent decades, there is still an urgent need to identify accurate transcriptome profile associated with the histological subtypes of NSCLC. The present study aims to identify the key dysregulated pathways and genes involved in the development of lung ADC and SCC and to relate them with the clinical traits. The transcriptional changes between tumour and normal lung tissues were investigated by RNA-seq. Gene ontology (GO), canonical pathways analysis with the prediction of upstream regulators, and weighted gene co-expression network analysis (WGCNA) to identify co-expressed modules and hub genes were used to explore the biological functions of the identified dysregulated genes. It was indicated that specific gene signatures differed significantly between ADC and SCC related to the distinct pathways. Of identified modules, four and two modules were the most related to clinical features in ADC and SCC, respectively. CTLA4, MZB1, NIP7, and BUB1B in ADC, as well as GNG11 and CCNB2 in SCC, are novel top hub genes in modules associated with tumour size, SUVmax, and recurrence-free survival. Our research provides a more effective understanding of the importance of biological pathways and the relationships between major genes in NSCLC in the perspective of searching for new molecular targets.

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“…Pharmacological inhibition of LSD1 leads to an activation of a neuronal differentiation program, driving MCC cells toward a normal Merkel cell fate and inducing cell cycle arrest and cell death. We show that LSD1 inhibitors lead to the disruption of the LSD1‐CoREST complex and the displacement and eventual degradation of the subunit HMG20B, similar to SNAG domain‐containing proteins that get released from the LSD1‐CoREST complex upon LSD1 inhibition in other cellular contexts (Ferrari‐Amorotti et al , 2013; Maiques‐Diaz et al , 2018; Egolf et al , 2019). Notably, HMG20B has previously been implicated in the repression of neuronal lineage‐specific genes (Hakimi et al , 2002; Ceballos‐Chávez et al , 2012).…”

Section: Discussionmentioning

confidence: 56%

“…Putting our findings in MCC in the broader context of studies investigating LSD1i treatment in other cancers, such as AMLs (Schenk et al , 2012; Somervaille et al , 2016; Fang et al , 2019; Cai et al , 2020), SCLC (Mohammad et al , 2015; Augert et al , 2019), prostate cancer (Sehrawat et al , 2018), and cutaneous squamous cell carcinoma (Egolf et al , 2019), it appears that in certain cellular lineages, the neuroendocrine lineage among them, LSD1 is a gate‐keeper of lineage plasticity. Inhibition of LSD1 may therefore represent a tractable entry point for differentiation therapies of solid cancers.…”

Section: Discussionmentioning

confidence: 85%

“…Importantly, we found that LSD1i treatment of MCC leads to dissociation of this complex, most notably loss of HMG20B binding (Figs 6D and EV5B). While pharmacological disruption of the LSD1‐CoREST complex is known to displace complex subunits, such as SNAG domain‐containing proteins (Saleque et al , 2007; Ferrari‐Amorotti et al , 2013; Maiques‐Diaz et al , 2018; Egolf et al , 2019), the loss of the HMG20B protein subunit has not been reported before.…”

Section: Resultsmentioning

confidence: 99%

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LSD1 inhibition induces differentiation and cell death in Merkel cell carcinoma

et al. 2020

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Merkel cell carcinoma (MCC) is a highly aggressive, neuroendocrine skin cancer that lacks actionable mutations, which could be utilized for targeted therapies. Epigenetic regulators governing cell identity may represent unexplored therapeutic entry points. Here, we targeted epigenetic regulators in a pharmacological screen and discovered that the lysine‐specific histone demethylase 1A (LSD1/KDM1A) is required for MCC growth in vitro and in vivo. We show that LSD1 inhibition in MCC disrupts the LSD1‐CoREST complex leading to displacement and degradation of HMG20B (BRAF35), a poorly characterized complex member that is essential for MCC proliferation. Inhibition of LSD1 causes derepression of transcriptional master regulators of the neuronal lineage, activates a gene expression signature resembling normal Merkel cells, and induces cell cycle arrest and cell death. Our study unveils the importance of LSD1 for maintaining cellular plasticity and proliferation in MCC. There is also growing evidence that cancer cells exploit cellular plasticity and dedifferentiation programs to evade destruction by the immune system. The combination of LSD1 inhibitors with checkpoint inhibitors may thus represent a promising treatment strategy for MCC patients.

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

Abstract: Highlights d LSD1 represses master epidermal transcription factors that promote differentiation d LSD1 inhibition activates the epidermal differentiation transcriptional program d LSD1 inhibition represses invasion in a model of cutaneous squamous cell carcinoma

Cited by 59 publications

References 75 publications

LSD1 represses a neonatal/reparative gene program in adult intestinal epithelium

LSD1 represses a neonatal/reparative gene program in adult intestinal epithelium

Molecular Signature of Subtypes of Non-Small-Cell Lung Cancer by Large-Scale Transcriptional Profiling: Identification of Key Modules and Genes by Weighted Gene Co-Expression Network Analysis (WGCNA)

LSD1 inhibition induces differentiation and cell death in Merkel cell carcinoma

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