LSD1 modulates the non-canonical integrin β3 signaling pathway in non-small cell lung carcinoma cells

Abstract

The epigenetic writer lysine-specific demethylase 1 (LSD1) is aberrantly upregulated in many cancer types and its overexpression correlates with poor survival and tumor progression. In this study, we analysed LSD1 function in non-small cell lung cancer adenocarcinomas. Expression profiling of 182 cases of lung adenocarcinoma proved a significant correlation of LSD1 overexpression with lung adenocarcinoma progression and metastasis. KRAS-mutated lung cancer cell clones were stably silenced for LSD1 expression. RNA-seq and comprehensive pathway analysis revealed, that genes related to a recently described non-canonical integrin β3 pathway, were significantly downregulated by LSD1 silencing. Hence, invasion and self-renewal capabilities were strongly decreased. Notably, this novel defined LSD1/integrin β3 axis, was also detected in human lung adenocarcinoma specimens. Furthermore, the linkage of LSD1 to an altered expression pattern of lung-lineage specific transcription factors and genes, which are involved in alveolar epithelial differentiation, was demonstrated. Thus, our findings point to a LSD1-integrin β3 axis, conferring attributes of invasiveness and tumor progression to lung adenocarcinoma.

LSD1 Inhibition Attenuates Tumor Growth by Disrupting PLK1 Mitotic Pathway

“…5B and C). In a previous study, we showed that LSD1 levels correlate with tumor grade in lung adenocarcinoma (26). As evident from Fig.…”

“…Previous work from our laboratory showed that LSD1 is overexpressed in lung adenocarcinomas and its expression correlates with tumor grade and invasive phenotypes (26). To identify the underlying molecular and cellular mechanisms associated with higher tumor cell proliferation in presence of LSD1, we investigated the impact of LSD1 inhibition in lung adenocarcinoma cells using the LSD1 inhibitor HCI-2509.…”

“…Staining was performed as described previously (26) on paraffin-embedded tumor sections of prepared tissue microarrays (TMA) consisting of 43 lung adenocarcinoma patients, using a-LSD1 and PLK1 antibodies as per the manufacturer's instructions. Staining intensities for LSD1 and PLK1 were calculated using QuPath (27), where the DAB channel intensity was extracted for each represented core of the TMA.…”

Preclinical studies reveal that LSD1 inhibition results in tumor growth arrest in lung adenocarcinoma independently of driver mutations

“…In the present study, we demonstrated that the LSD1 inhibitor HCI-2509 inhibits LUAD cell growth in a dose-dependent manner in vitro and in vivo. Because overexpression of LSD1 was observed in many cancer types, including NSCLC, inhibition of LSD1 was suggested as a promising therapeutical option (Lv et al, 2012;Lim et al, 2017). Surprisingly, in contrast to treatment studies on acute myeloid leukemia and smallcell lung cancer (Mohammad et al, 2015;Stazi et al, 2016), conventional MAO-based LSD1 inhibitors neither affected the histone methylation status, nor influenced NSCLC cell growth.…”

“…LSD1 is an epigenetic eraser that is drastically upregulated in various tumor types (Kahl et al, 2006;Schulte et al, 2009;Lim et al, 2010;Lin et al, 2011). In particular, LSD1 overexpression in NSCLC is associated with high malignancy and a poor prognosis (Lv et al, 2012;Lim et al, 2017).…”