Abstract
Keratin 6A (KRT6A) belongs to the keratin protein family which is a critical component of cytoskeleton in mammalian cells. Although KRT6A upregulation in non-small cell lung cancer (NSCLC) has been reported, the regulatory mechanism and functional role of KRT6A in NSCLC development have been less well investigated. In this study, KRT6A was confirmed to be highly expressed in NSCLC tissue samples, and its high expression correlated with poor patient prognosis. Furthermore, overexpression of KRT6A promotes NSCLC cell proliferation and invasion. Mechanistically, KRT6A overexpression is sufficient to upregulate glucose-6-phosphate dehydrogenase (G6PD) levels and increase the pentose phosphate pathway flux, an essential metabolic pathway to support cancer cell growth and invasion. In addition, we discovered that lysine-specific demethylase 1A (LSD1) functions upstream to promote KRT6A gene expression. We also found that the MYC family members c-MYC/MYCN are involved in KRT6A-induced G6PD upregulation. Therefore, this study reveals an underappreciated mechanism that KRT6A acts downstream of LSD1 and functions as a pivotal driver for NSCLC progression by upregulating G6PD through the MYC signaling pathway. Together, KRT6A and LSD1 may serve as potential prognostic indictors and therapeutic targets for NSCLC.
Highlights
Lung cancer is the most common cause of cancer related death in the world and China, especially among males (Torre et al, 2015; Feng et al, 2019)
Keratin 6A (KRT6A) expression was significantly higher in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) than normal tissues
Recent studies revealed that high expression of KRT6A is associated with unfavorable prognosis of lung cancer patients (Xiao et al, 2017)
Summary
Lung cancer is the most common cause of cancer related death in the world and China, especially among males (Torre et al, 2015; Feng et al, 2019). There are two main histological subtypes of lung cancer, known as small cell lung cancer (SCLC) and non-SCLC (NSCLC). 85% of lung cancer cases are attributed to NSCLC, and the most common subtypes of NSCLC are lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD) (Molina et al, 2008). The overall cure and survival rate of NSCLC remain low (Herbst et al, 2018). The high mortality of lung cancer patients is primarily due to the fact that more than half of NSCLC patients already developed metastasis at diagnosis (Herbst et al, 2008; Scrima et al, 2017). Exploring the molecular mechanisms of NSCLC invasion and metastasis will help improve the therapeutic response and survival of NSCLC patients
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