KDM1A promotes tumor cell invasion by silencing TIMP3 in non-small cell lung cancer cells
KDM1A promotes non-small cell lung cancer metastasis by demethylating H3K4me2 to silence TIMP3, activating MMP2 and JNK to drive invasion.
Published Apr 2, 201647 citationsPaper ↗
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The study earns praise for a clean KDM1A-TIMP3-MMP2/JNK rescue axis and pharmacological validation, though its mechanism hinges on unproven direct promoter binding and its prognosis claims rest on expression ratios without intervention data, leaving the therapy…
Abstract
// Lingzhi Kong 1, 4, * , Peng Zhang 2, * , Wang Li 1, 4 , Yan Yang 1, 4 , Ye Tian 1, 4 , Xujun Wang 1, 4 , Sujun Chen 1, 4 , Yuxin Yang 1, 4 , Tianhao Huang 1, 4 , Tian Zhao 1, 4 , Liang Tang 3 , Bo Su 3 , Fei Li 5 , X. Shirley Liu 1, 4, 6 , Fan Zhang 1, 4 1 Clinical Translational Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China 2 Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China 3 The Central Laboratory, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China 4 School of Life Science and Technology, Tongji University, Shanghai 200092, China 5 Department of Biology, New York University, New York, NY 10003, USA 6 Department 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: fzhang@tongji.edu.cn 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.