Abstract
Epigenetic regulation plays an important role in tumor metastasis. KDM1A is a histone demethylase specific for H3K4me2/me1 demethylation, and has been found to be overexpressed in many cancers, including non-small cell lung cancer (NSCLC). However, the role of KDM1A in lung cancer remains unclear. Here, we show that KDM1A promotes cancer metastasis in NSCLC cells by repressing TIMP3 (tissue inhibitor of metalloproteinase 3) expression. Consistently with this, overexpression of TIMP3 inhibited MMP2 expression and JNK phosphorylation, both of which are known to be important for cell invasion and migration. Importantly, knockdown of TIMP3 in KDM1A-deficient cells rescued the metastatic capability of NSCLC cells. These findings were also confirmed by pharmacological inhibition assays. We further demonstrate that KDM1A removes H3K4me2 at the promoter of TIMP3, thus repressing the transcription of TIMP3. Finally, high expression of KDM1A and low expression of TIMP3 significantly correlate with a poor prognosis in NSCLC patients. This study establishes a mechanism by which KDM1A promotes cancer metastasis in NSCLC cells, and we suggest that KDM1A may be a potential therapeutic target for NSCLC treatment.
Highlights
Non-small cell lung cancer (NSCLC) is one of the most common cancers and is the leading cause of death from cancer in men worldwide [1]
We found that KDM1A was up-regulated in tumors compared to non-tumor controls and significantly upregulated in all stages of non-small cell lung cancer (NSCLC), from stage 1 (T1) to stage 4 (T4) (Figure 1A and 1B)
We demonstrate that KDM1A promotes tumor metastasis both in vitro and in vivo, and its higher expression is significantly correlated with poor prognosis in NSCLC patients
Summary
Non-small cell lung cancer (NSCLC) is one of the most common cancers and is the leading cause of death from cancer in men worldwide [1]. How epigenetic dysregulation promotes the gain of tumorigenicity, for example, in NSCLC cells, remains unknown. KDM1A, known as LSD1 or AOF2, demethylates mono- and dimethylated H3K4 (H3K4me and H3K4me1) [5, 6]. It functions as a transcriptional co-repressor within the repressive chromatin complex, which includes Co-REST as well as HDAC1/2 [7,8,9]. Overexpression of KDM1A contributes to tumorigenesis in many types of cancer [10]. It has recently been shown that overexpression of KDM1A promotes proliferation, migration and invasion in NSCLC cells www.impactjournals.com/oncotarget [11]. Key target genes and signaling pathways that are regulated by KDM1A in NSCLC remain poorly understood
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