KDM1A promotes tumor cell invasion by silencing TIMP3 in non-small cell lung cancer cells

Lingzhi Kong, Peng Zhang, Wang Li, Yan Yang, Ye Tian, Xujun Wang, Sujun Chen, Yuxin Yang, Tianhao Huang, Tian Zhao, Liang Tang, Bo Su, Fei Li, X Shirley Liu, Fan Zhang

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournalOncotarget
DOIs
StatePublished - Apr 2 2016

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Tissue Inhibitor of Metalloproteinase-3
Non-Small Cell Lung Carcinoma
Neoplasms
Neoplasm Metastasis
Histone Demethylases
Epigenomics
Cell Movement
Lung Neoplasms
Phosphorylation
Pharmacology
Therapeutics

Cite this

KDM1A promotes tumor cell invasion by silencing TIMP3 in non-small cell lung cancer cells. / Kong, Lingzhi; Zhang, Peng; Li, Wang; Yang, Yan; Tian, Ye; Wang, Xujun; Chen, Sujun; Yang, Yuxin; Huang, Tianhao; Zhao, Tian; Tang, Liang; Su, Bo; Li, Fei; Liu, X Shirley; Zhang, Fan.

In: Oncotarget, 02.04.2016.

Research output: Contribution to journalArticle

Kong, L, Zhang, P, Li, W, Yang, Y, Tian, Y, Wang, X, Chen, S, Yang, Y, Huang, T, Zhao, T, Tang, L, Su, B, Li, F, Liu, XS & Zhang, F 2016, 'KDM1A promotes tumor cell invasion by silencing TIMP3 in non-small cell lung cancer cells', Oncotarget. https://doi.org/10.18632/oncotarget.8563
Kong, Lingzhi ; Zhang, Peng ; Li, Wang ; Yang, Yan ; Tian, Ye ; Wang, Xujun ; Chen, Sujun ; Yang, Yuxin ; Huang, Tianhao ; Zhao, Tian ; Tang, Liang ; Su, Bo ; Li, Fei ; Liu, X Shirley ; Zhang, Fan. / KDM1A promotes tumor cell invasion by silencing TIMP3 in non-small cell lung cancer cells. In: Oncotarget. 2016.
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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.",
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