title: TET1 suppresses cancer invasion by activating the tissue inhibitors of metalloproteinases.
abstract: Tumor suppressor gene silencing through cytosine methylation contributes to cancer formation. Whether DNA demethylation enzymes counteract this oncogenic effect is unknown. Here, we show that TET1, a dioxygenase involved in cytosine demethylation, is downregulated in prostate and breast cancer tissues. TET1 depletion facilitates cell invasion, tumor growth, and cancer metastasis in prostate xenograft models and correlates with poor survival rates in breast cancer patients. Consistently, enforced expression of TET1 reduces cell invasion and breast xenograft tumor formation. Mechanistically, TET1 suppresses cell invasion through its dioxygenase and DNA binding activities. Furthermore, TET1 maintains the expression of tissue inhibitors of metalloproteinase (TIMP) family proteins 2 and 3 by inhibiting their DNA methylation. Concurrent low expression of TET1 and TIMP2 or TIMP3 correlates with advanced node status in clinical samples. Together, these results illustrate a mechanism by which TET1 suppresses tumor development and invasion partly through downregulation of critical gene methylation.
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei 115, Taiwan, ROC.
authors.forename: Chih-Hung
authors.initials: CH
authors.lastname: Hsu
authors.forename: Kai-Lin
authors.initials: KL
authors.lastname: Peng
authors.forename: Ming-Lun
authors.initials: ML
authors.lastname: Kang
authors.forename: Yi-Ren
authors.initials: YR
authors.lastname: Chen
authors.forename: Yu-Chih
authors.initials: YC
authors.lastname: Yang
authors.forename: Chin-Hsien
authors.initials: CH
authors.lastname: Tsai
authors.forename: Chi-Shen
authors.initials: CS
authors.lastname: Chu
authors.forename: Yung-Ming
authors.initials: YM
authors.lastname: Jeng
authors.forename: Yen-Ting
authors.initials: YT
authors.lastname: Chen
authors.forename: Feng-Mao
authors.initials: FM
authors.lastname: Lin
authors.forename: Hsien-Da
authors.initials: HD
authors.lastname: Huang
authors.forename: Yun-Yuh
authors.initials: YY
authors.lastname: Lu
authors.forename: Yu-Ching
authors.initials: YC
authors.lastname: Teng
authors.forename: Shinn-Tsuen
authors.initials: ST
authors.lastname: Lin
authors.forename: Ruo-Kai
authors.initials: RK
authors.lastname: Lin
authors.forename: Fan-Mei
authors.initials: FM
authors.lastname: Tang
authors.forename: Sung-Bau
authors.initials: SB
authors.lastname: Lee
authors.forename: Huan Ming
authors.initials: HM
authors.lastname: Hsu
authors.forename: Jyh-Cherng
authors.initials: JC
authors.lastname: Yu
authors.forename: Pei-Wen
authors.initials: PW
authors.lastname: Hsiao
authors.forename: Li-Jung
authors.initials: LJ
authors.lastname: Juan
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019175:DNA Methylation / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D049308:Dioxygenases / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D006899:Mixed Function Oxygenases; D009361:Neoplasm Invasiveness; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000096:biosynthesis* / Q000235:genetics; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000096:biosynthesis* / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; C560823:TIMP2 protein, human; C088390:TIMP3 protein, human; D019717:Tissue Inhibitor of Metalloproteinase-3; D025521:Tumor Suppressor Proteins; D019716:Tissue Inhibitor of Metalloproteinase-2; D006899:Mixed Function Oxygenases; C462539:TET1 protein, human; D049308:Dioxygenases