title: TET1 is a tumour suppressor that inhibits colon cancer growth by derepressing inhibitors of the WNT pathway.
abstract: Ten eleven translocation (TET) enzymes catalyse the oxidative reactions of 5-methylcytosine (5mC) to promote the demethylation process. The reaction intermediate 5-hydroxymethylcytosine (5hmC) has been shown to be abundant in embryonic stem cells and tissues but strongly depleted in human cancers. Genetic mutations of TET2 gene were associated with leukaemia, whereas TET1 downregulation has been shown to promote malignancy in breast cancer. Here we report that TET1 is downregulated in colon tumours from the initial stage. TET1 silencing in primary epithelial colon cells increase their cellular proliferation while its re-expression in colon cancer cells inhibits their proliferation and the growth of tumour xenografts even at later stages. We found that TET1 binds to the promoter of the DKK gene inhibitors of the WNT signalling to maintain them hypomethylated. Downregulation of TET1 during colon cancer initiation leads to repression, by DNA methylation, the promoters of the inhibitors of the WNT pathway resulting in a constitutive activation of the WNT pathway. Thus the DNA hydroxymethylation mediated by TET1 controlling the WNT signalling is a key player of tumour growth. These results provide new insights for understanding how tumours escape cellular controls.
authors.affiliation: Epigenetics, Human Genetics Foundation (HuGeF), Torino, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Neri
authors.affiliation: Epigenetics, Human Genetics Foundation (HuGeF), Torino, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Dettori
authors.affiliation: 1] Epigenetics, Human Genetics Foundation (HuGeF), Torino, Italy [2] Dipartimento di Biotecnologie Chimica e Farmacia, Università di Siena, Siena, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Incarnato
authors.affiliation: 1] Epigenetics, Human Genetics Foundation (HuGeF), Torino, Italy [2] Dipartimento di Biotecnologie Chimica e Farmacia, Università di Siena, Siena, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Krepelova
authors.affiliation: 1] Epigenetics, Human Genetics Foundation (HuGeF), Torino, Italy [2] Dipartimento di Biotecnologie Chimica e Farmacia, Università di Siena, Siena, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Rapelli
authors.affiliation: Epigenetics, Human Genetics Foundation (HuGeF), Torino, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Maldotti
authors.affiliation: Epigenetics, Human Genetics Foundation (HuGeF), Torino, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Parlato
authors.affiliation: Dipartimento di Scienze Chirurgiche, Microchirurgiche e Mediche, Università di Sassari, Sassari, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Paliogiannis
authors.affiliation: 1] Epigenetics, Human Genetics Foundation (HuGeF), Torino, Italy [2] Dipartimento di Scienze della Vita e Biologia dei Sistemi, Università di Torino Torino, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Oliviero
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D015153:Blotting, Western; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D006899:Mixed Function Oxygenases; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000187:drug effects / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000903:Antibiotics, Antineoplastic; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; D004317:Doxorubicin; D006899:Mixed Function Oxygenases; C462539:TET1 protein, human