Universität zu Köln

Dalvi, Priya S., Kacheleidt, Iris F., Lim, So-Young, Meemboor, Sonja, Mueller, Marion, Eischeid-Scholz, Hannah, Schaefer, Stephan C., Buettner, Reinhard, Klein, Sebastian and Odenthal, Margarete ORCID: 0000-0002-2424-0960 (2019). LSD1 Inhibition Attenuates Tumor Growth by Disrupting PLK1 Mitotic Pathway. Mol. Cancer Res., 17 (6). S. 1326 - 1338. PHILADELPHIA: AMER ASSOC CANCER RESEARCH. ISSN 1557-3125

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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 1/4 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-transitionmediating proliferation of tumor cells and suggest targeting the LSD1/ PLK1 axis as a novel therapeutic approach for lung adenocarcinoma treatment.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Dalvi, Priya S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kacheleidt, Iris F. UNSPECIFIED UNSPECIFIED UNSPECIFIED Lim, So-Young UNSPECIFIED UNSPECIFIED UNSPECIFIED Meemboor, Sonja UNSPECIFIED UNSPECIFIED UNSPECIFIED Mueller, Marion UNSPECIFIED UNSPECIFIED UNSPECIFIED Eischeid-Scholz, Hannah UNSPECIFIED UNSPECIFIED UNSPECIFIED Schaefer, Stephan C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Buettner, Reinhard UNSPECIFIED UNSPECIFIED UNSPECIFIED Klein, Sebastian UNSPECIFIED UNSPECIFIED UNSPECIFIED Odenthal, Margarete UNSPECIFIED orcid.org/0000-0002-2424-0960 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-146834
DOI:	10.1158/1541-7786.MCR-18-0971
Journal or Publication Title:	Mol. Cancer Res.
Volume:	17
Number:	6
Page Range:	S. 1326 - 1338
Date:	2019
Publisher:	AMER ASSOC CANCER RESEARCH
Place of Publication:	PHILADELPHIA
ISSN:	1557-3125
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language EPIGENETIC MODIFICATION CONTRIBUTES; POLO-LIKE KINASE-1; CELL LUNG-CANCER; STEM-CELLS; DEMETHYLASE; HISTONE; PROLIFERATION; EXPRESSION; CYTOKINESIS; ALPHA Multiple languages Oncology; Cell Biology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/14683