title: KDM1A promotes tumor cell invasion by silencing TIMP3 in non-small cell lung cancer cells.
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.
authors.affiliation: Clinical Translational Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China.|School of Life Science and Technology, Tongji University, Shanghai 200092, China.
authors.forename: Lingzhi
authors.initials: L
authors.lastname: Kong
authors.affiliation: Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Clinical Translational Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China.|School of Life Science and Technology, Tongji University, Shanghai 200092, China.
authors.forename: Wang
authors.initials: W
authors.lastname: Li
authors.affiliation: Clinical Translational Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China.|School of Life Science and Technology, Tongji University, Shanghai 200092, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Clinical Translational Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China.|School of Life Science and Technology, Tongji University, Shanghai 200092, China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Clinical Translational Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China.|School of Life Science and Technology, Tongji University, Shanghai 200092, China.
authors.forename: Xujun
authors.initials: X
authors.lastname: Wang
authors.affiliation: Clinical Translational Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China.|School of Life Science and Technology, Tongji University, Shanghai 200092, China.
authors.forename: Sujun
authors.initials: S
authors.lastname: Chen
authors.affiliation: Clinical Translational Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China.|School of Life Science and Technology, Tongji University, Shanghai 200092, China.
authors.forename: Yuxin
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Clinical Translational Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China.|School of Life Science and Technology, Tongji University, Shanghai 200092, China.
authors.forename: Tianhao
authors.initials: T
authors.lastname: Huang
authors.affiliation: Clinical Translational Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China.|School of Life Science and Technology, Tongji University, Shanghai 200092, China.
authors.forename: Tian
authors.initials: T
authors.lastname: Zhao
authors.affiliation: The Central Laboratory, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Tang
authors.affiliation: The Central Laboratory, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Su
authors.affiliation: Department of Biology, New York University, New York, NY 10003, USA.
authors.forename: Fei
authors.initials: F
authors.lastname: Li
authors.affiliation: Clinical Translational Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China.|School of Life Science and Technology, Tongji University, Shanghai 200092, China.|Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard School of Public Health, Boston, MA 02215, USA.
authors.forename: X Shirley
authors.initials: XS
authors.lastname: Liu
authors.affiliation: Clinical Translational Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China.|School of Life Science and Technology, Tongji University, Shanghai 200092, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D020868:Gene Silencing; D064593:Heterografts; D056466:Histone Demethylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000235:genetics; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C088390:TIMP3 protein, human; D019717:Tissue Inhibitor of Metalloproteinase-3; D056466:Histone Demethylases; C495195:KDM1A protein, human
keywords: H3K4me2; JNK; KDM1A; TIMP3; non-small cell lung cancer