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.
Highlights
Lung cancer is the leading cause of cancer-related deaths worldwide
The highest lysine-specific demethylase 1 (LSD1) expression levels were detected in small cell lung cancer (SCLC), which is associated with the worst prognosis[22] (Fig. 1A)
Albeit LSD1 expression was lower in AC than in other lung cancer types, immunohistology on lung AC compared with non-tumorous lung tissues implies that LSD1 is overexpressed in AC (Fig. 1B)
Summary
Lung cancer is the leading cause of cancer-related deaths worldwide. The high mortality associated with lung cancer is partly due to metastasis before surgical removal of the primary tumor[1]. Seguin et al showed that activation of the integrin αvβ[3] complex by non-canonical ligand galectin-3 binding recruits KRAS to the tumor cell plasma membrane, which in turn results in a prominent RalB and NF-κB activation[7]. This non-canonical integrin αvβ3-KRAS-NF-κB signal axis serves as a driving force for breast, lung and pancreatic carcinomas with stem-like properties, that are highly aggressive and resistant to receptor tyrosine kinase inhibitors such as erlotinib[7]. Our findings provide a rationale to overcome cancer stemness and metastasis by targeting LSD1 in NSCLC in future therapeutic strategies
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