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| Status |
Public on Sep 04, 2020 |
| Title |
Transcriptomic maps of pharmacological LSD1 inhibition in MCC [SLAMseq] |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
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 proliferation and maintaining cell identity in MCC. There is 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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| Overall design |
Gene expression profiling of PeTa cell line upon pharmacological LSD1 inhibitor treatment by 3'-mRNA sequencing. PeTa cells were pre-treated for 30min with 100nM GSK-LSD1 and newly synthesized transcripts were labeled with 500uM 4-thiouridine for 1 or 6h.
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| Contributor(s) |
Leiendecker L, Jung PS, Krecioch I, Neumann T, Schleiffer A, Mechtler K, Wiesner T, Obenauf AC |
| Citation(s) |
33026191 |
| |
| Submission date |
Mar 31, 2020 |
| Last update date |
Dec 04, 2020 |
| Contact name |
Anna Obenauf |
| Organization name |
IMP - Research Institute of Molecular Pathology
|
| Lab |
Anna Obenauf
|
| Street address |
Campus-Vienna-Biocenter 1
|
| City |
Vienna |
| State/province |
Vienna |
| ZIP/Postal code |
1030 |
| Country |
Austria |
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| Platforms (1) |
| GPL11154 |
Illumina HiSeq 2000 (Homo sapiens) |
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| Samples (12)
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| This SubSeries is part of SuperSeries: |
| GSE147817 |
Pharmacological LSD1 inhibition in MCC |
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| Relations |
| BioProject |
PRJNA621228 |
| SRA |
SRP254771 |
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