Oncotarget

Research Papers:

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 and Fan Zhang _

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Oncotarget. 2016; 7:27959-27974. https://doi.org/10.18632/oncotarget.8563

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Abstract

Lingzhi Kong1,4,*, Peng Zhang2,*, Wang Li1,4, Yan Yang1,4, Ye Tian1,4, Xujun Wang1,4, Sujun Chen1,4, Yuxin Yang1,4, Tianhao Huang1,4, Tian Zhao1,4, Liang Tang3, Bo Su3, Fei Li5, X. Shirley Liu1,4,6, Fan Zhang1,4

1Clinical Translational Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China

2Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China

3The Central Laboratory, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China

4School of Life Science and Technology, Tongji University, Shanghai 200092, China

5Department of Biology, New York University, New York, NY 10003, USA

6Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard School of Public Health, Boston, MA 02215, USA

*These authors contributed equally to this work

Correspondence to:

Fan Zhang, e-mail: [email protected]

Keywords: KDM1A, H3K4me2, TIMP3, JNK, non-small cell lung cancer

Received: September 07, 2015     Accepted: March 26, 2016     Published: April 02, 2016

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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