LSD1 inhibition induces differentiation and cell death in Merkel cell carcinoma
Abstract 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 regul...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Springer Nature
2020-10-01
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| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.202012525 |
| _version_ | 1827015196729671680 |
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| author | Lukas Leiendecker Pauline S Jung Izabela Krecioch Tobias Neumann Alexander Schleiffer Karl Mechtler Thomas Wiesner Anna C Obenauf |
| author_facet | Lukas Leiendecker Pauline S Jung Izabela Krecioch Tobias Neumann Alexander Schleiffer Karl Mechtler Thomas Wiesner Anna C Obenauf |
| author_sort | Lukas Leiendecker |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-03-07T16:41:09Z |
| format | Article |
| id | doaj.art-3e160d333a2f40228b3fd40c2109df55 |
| institution | Directory Open Access Journal |
| issn | 1757-4676 1757-4684 |
| language | English |
| last_indexed | 2025-02-18T14:18:40Z |
| publishDate | 2020-10-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-3e160d333a2f40228b3fd40c2109df552024-10-28T08:54:44ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842020-10-01121112210.15252/emmm.202012525LSD1 inhibition induces differentiation and cell death in Merkel cell carcinomaLukas Leiendecker0Pauline S Jung1Izabela Krecioch2Tobias Neumann3Alexander Schleiffer4Karl Mechtler5Thomas Wiesner6Anna C Obenauf7Research Institute of Molecular Pathology (IMP), Vienna BioCenter (VBC)Research Institute of Molecular Pathology (IMP), Vienna BioCenter (VBC)Research Institute of Molecular Pathology (IMP), Vienna BioCenter (VBC)Research Institute of Molecular Pathology (IMP), Vienna BioCenter (VBC)Research Institute of Molecular Pathology (IMP), Vienna BioCenter (VBC)Institute of Molecular Biotechnology (IMBA), Vienna BioCenter (VBC)Department of Dermatology, Medical University of ViennaResearch Institute of Molecular Pathology (IMP), Vienna BioCenter (VBC)Abstract 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.https://doi.org/10.15252/emmm.202012525epigeneticsHMG20BLSD1merkel cell carcinomatargeted therapy |
| spellingShingle | Lukas Leiendecker Pauline S Jung Izabela Krecioch Tobias Neumann Alexander Schleiffer Karl Mechtler Thomas Wiesner Anna C Obenauf LSD1 inhibition induces differentiation and cell death in Merkel cell carcinoma EMBO Molecular Medicine epigenetics HMG20B LSD1 merkel cell carcinoma targeted therapy |
| title | LSD1 inhibition induces differentiation and cell death in Merkel cell carcinoma |
| title_full | LSD1 inhibition induces differentiation and cell death in Merkel cell carcinoma |
| title_fullStr | LSD1 inhibition induces differentiation and cell death in Merkel cell carcinoma |
| title_full_unstemmed | LSD1 inhibition induces differentiation and cell death in Merkel cell carcinoma |
| title_short | LSD1 inhibition induces differentiation and cell death in Merkel cell carcinoma |
| title_sort | lsd1 inhibition induces differentiation and cell death in merkel cell carcinoma |
| topic | epigenetics HMG20B LSD1 merkel cell carcinoma targeted therapy |
| url | https://doi.org/10.15252/emmm.202012525 |
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