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Molecular Cancer Research
Molecular Cancer Research

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Chromatin, Epigenetics and RNA Regulation

LSD1 Inhibition Attenuates Tumor Growth by Disrupting PLK1 Mitotic Pathway

Priya S. Dalvi, Iris F. Macheleidt, So-Young Lim, Sonja Meemboor, Marion Müller, Hannah Eischeid-Scholz, Stephan C. Schaefer, Reinhard Buettner, Sebastian Klein and Margarete Odenthal
Priya S. Dalvi
Institute of Pathology, University Hospital of Cologne, Cologne, Germany.Center for Molecular Medicine Cologne, Cologne, Germany.
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Iris F. Macheleidt
Institute of Pathology, University Hospital of Cologne, Cologne, Germany.Center for Molecular Medicine Cologne, Cologne, Germany.
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So-Young Lim
Institute of Pathology, University Hospital of Cologne, Cologne, Germany.Center for Molecular Medicine Cologne, Cologne, Germany.
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Sonja Meemboor
Institute of Pathology, University Hospital of Cologne, Cologne, Germany.Center for Molecular Medicine Cologne, Cologne, Germany.
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Marion Müller
Institute of Pathology, University Hospital of Cologne, Cologne, Germany.
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Hannah Eischeid-Scholz
Institute of Pathology, University Hospital of Cologne, Cologne, Germany.
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Stephan C. Schaefer
Institute of Pathology, University Hospital of Cologne, Cologne, Germany.Center for Integrated Oncology Cologne Bonn, Cologne, Germany.Lung Cancer Group Cologne, University Hospital of Cologne, Cologne, Germany.
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Reinhard Buettner
Institute of Pathology, University Hospital of Cologne, Cologne, Germany.Center for Molecular Medicine Cologne, Cologne, Germany.Center for Integrated Oncology Cologne Bonn, Cologne, Germany.Lung Cancer Group Cologne, University Hospital of Cologne, Cologne, Germany.
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Sebastian Klein
Institute of Pathology, University Hospital of Cologne, Cologne, Germany.Department of Translational Genomics, University of Cologne, Cologne, Germany.Else Kröner Forschungskolleg Cologne, University Hospital of Cologne, Cologne, Germany.
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Margarete Odenthal
Institute of Pathology, University Hospital of Cologne, Cologne, Germany.Center for Molecular Medicine Cologne, Cologne, Germany.
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  • ORCID record for Margarete Odenthal
  • For correspondence: m.odenthal@uni-koeln.de
DOI: 10.1158/1541-7786.MCR-18-0971 Published June 2019
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Abstract

Lysine-specific demethylase 1 (LSD1) is a histone modifier that is highly overexpressed in lung adenocarcinoma, which results in aggressive tumor biology. Tumor cell proliferation and migration analysis after LSD1 inhibition in the lung adenocarcinoma cell line PC9, using the LSD1 inhibitor HCI-2509 and siRNA, demonstrated that LSD1 activity was essential for proliferation and migration capacities of tumor cells. Moreover, reduced proliferation rates after LSD1 inhibition were shown to be associated with a cell-cycle arrest of the tumor cells in the G2–M-phase. Expression profiling followed by functional classification and pathway analysis indicated prominent repression of the polo-like kinase 1 (PLK1) pathway upon LSD1 inhibition. In contrast, transient overexpression of exogenous PLK1 plasmid rescued the LSD1 inhibition–mediated downregulation of PLK1 pathway genes. Mechanistically, LSD1 directly regulates expression of PLK1 by binding to its promoter region that subsequently affects expression of its downstream target genes. Notably, using lung adenocarcinoma TCGA datasets a significant correlation between LSD1 and PLK1 along with its downstream targets was observed. Furthermore, the LSD1/PLK1 linkage was confirmed by IHC analysis in a clinical lung adenocarcinoma cohort (n = 43). Conclusively, this is the first study showing a direct transcriptional link between LSD1 and PLK1.

Implications: These findings point to a role of LSD1 in regulating PLK1 and thus efficient G2–M-transition–mediating proliferation of tumor cells and suggest targeting the LSD1/PLK1 axis as a novel therapeutic approach for lung adenocarcinoma treatment.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/).

  • Mol Cancer Res 2019;17:1326–37

  • Received September 12, 2018.
  • Revision received January 16, 2019.
  • Accepted February 8, 2019.
  • Published first February 13, 2019.
  • ©2019 American Association for Cancer Research.
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Molecular Cancer Research: 17 (6)
June 2019
Volume 17, Issue 6
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LSD1 Inhibition Attenuates Tumor Growth by Disrupting PLK1 Mitotic Pathway
Priya S. Dalvi, Iris F. Macheleidt, So-Young Lim, Sonja Meemboor, Marion Müller, Hannah Eischeid-Scholz, Stephan C. Schaefer, Reinhard Buettner, Sebastian Klein and Margarete Odenthal
Mol Cancer Res June 1 2019 (17) (6) 1326-1337; DOI: 10.1158/1541-7786.MCR-18-0971

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LSD1 Inhibition Attenuates Tumor Growth by Disrupting PLK1 Mitotic Pathway
Priya S. Dalvi, Iris F. Macheleidt, So-Young Lim, Sonja Meemboor, Marion Müller, Hannah Eischeid-Scholz, Stephan C. Schaefer, Reinhard Buettner, Sebastian Klein and Margarete Odenthal
Mol Cancer Res June 1 2019 (17) (6) 1326-1337; DOI: 10.1158/1541-7786.MCR-18-0971
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