Neri F, Dettori D, Incarnato D, Krepelova A, Rapelli S, Maldotti M, Parlato C, Paliogiannis P, Oliviero S
Epigenetics, Human Genetics Foundation (HuGeF), Torino, Italy.
1] Epigenetics, Human Genetics Foundation (HuGeF), Torino, Italy [2] Dipartimento di Biotecnologie Chimica e Farmacia, Università di Siena, Siena, Italy.
Oncogene. 2015 Aug 6;34(32):4168-76. doi: 10.1038/onc.2014.356. Epub 2014 Nov 3.
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.
10-11易位(TET)酶催化5-甲基胞嘧啶(5mC)的氧化反应,以促进去甲基化过程。反应中间体5-羟甲基胞嘧啶(5hmC)已被证明在胚胎干细胞和组织中含量丰富,但在人类癌症中则显著减少。TET2基因的基因突变与白血病有关,而TET1的下调已被证明可促进乳腺癌的恶性发展。在此,我们报告TET1在结肠癌的初始阶段即被下调。原代结肠上皮细胞中TET1的沉默会增加其细胞增殖,而其在结肠癌细胞中的重新表达即使在后期也会抑制其增殖以及肿瘤异种移植物的生长。我们发现TET1与WNT信号通路的DKK基因抑制剂的启动子结合,以维持它们的低甲基化状态。结肠癌起始过程中TET1的下调会导致WNT通路抑制剂的启动子因DNA甲基化而受到抑制,从而导致WNT通路的组成性激活。因此,由TET1介导的控制WNT信号通路的DNA羟甲基化是肿瘤生长的关键因素。这些结果为理解肿瘤如何逃避细胞控制提供了新的见解。