LSD1 inhibition attenuates tumor growth by disrupting PLK1 mitotic pathway.

Related Articles

LSD1 inhibition attenuates tumor growth by disrupting PLK1 mitotic pathway.

Mol Cancer Res. 2019 Feb 13;:

Authors: Dalvi PS, Macheleidt IF, Lim SY, Meemboor S, Muller M, Eischeid-Scholz H, Schaefer SC, Buettner R, Klein S, Odenthal M

Abstract
Lysine-specific demethylase 1 (LSD1) is a histone modifier that is highly overexpressed in lung adenocarcinoma (LUAD), which results in aggressive tumor biology. Tumor cell proliferation and migration analysis after LSD1 inhibition in the LUAD 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 LUAD TCGA datasets a significant correlation between LSD1 and PLK1 along with its downstream targets was observed. Furthermore, the LSD1/PLK1 linkage was confirmed by immunohistochemical analysis in a clinical LUAD 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 LUAD treatment.

PMID: 30760542 [PubMed - as supplied by publisher]

from A via a.sfakia on Inoreader http://bit.ly/2EdA53n