Ten-eleven translocation methylcytosine dioxygenase 1 (TET1) is a member of the TET family of enzymes that in humans is encoded by the TET1 gene.[1][2]
TET1 was first discovered in a 61-year-old patient with a rare variation of t(10;11)(q22;q23) acute myeloid leukemia(AML) as a zinc-finger binding protein (specifically on the CXXC domain) that fuses to the gene MLL.[3] Another study confirmed that this protein was a translocation partner of MLL in an 8-year-old patient with t(10;11)(q22;q23) AML and named the protein Ten-Eleven Translocation 1.[4]
Function
TET1 catalyzes the conversion of the modified DNA base 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC).[5] TET1 produces 5-hmC by oxidation of 5-mC in an iron and alpha-ketoglutarate dependent manner.[6] The conversion of 5-mC to 5-hmC has been proposed as the initial step of active DNA demethylation in mammals.[6] Additionally, downgrading TET1 has decreased levels of 5-formylcytosine (5-fC) and 5-carboxylcytosine (5-caC) in both cell cultures and mice.[6]
Colon, breast, prostate and liver tumors have significantly reduced levels of TET1 compared to the healthy colon cells and normal epithelial colon cells with downgraded TET1 levels have greater levels of proliferation.[10][11][12][13] Additionally, increasing TET1 expression levels in colon cancer cells decreased cell proliferation in both cell cultures and mice through demethylation of promoters of the WNT signaling pathway.[11]
Breast cancer cell lines with silenced TET1 expression have increased rates of invasion and breast cancers that spread to the lymph nodes are characterized by lower TET1 levels.[14] TET1 levels could be used to detect breast cancer metastasis.[14] A histone deacetylase inhibitor Trichostatin A increased levels of TET1 in breast cancer tissues but was a less effective tumor suppressor in patients with low TET1 expression.[15] Breast cancer patients with high TET1 levels had significantly higher survival probabilities than patients with low TET1 levels.[13]
Degradation of TET1 in hypoxia-induced EMT lung cancer cells led to reduced metastasis rates and cells.[16] Healthy cells transitioning to cancer cells have decreased levels of TET1 but decreasing TET1 expression does not lead to malignancy.[17] Cancer cells using the KRAS pathway had decreased invasive potential after reintroducing TET1, likewise downgrading KRAS increased TET1 levels.[18]
↑Ono R, Taki T, Taketani T, Taniwaki M, Kobayashi H, Hayashi Y (July 2002). "LCX, leukemia-associated protein with a CXXC domain, is fused to MLL in acute myeloid leukemia with trilineage dysplasia having t(10;11)(q22;q23)". Cancer Research. 62 (14): 4075–80. PMID12124344.
↑Lorsbach RB, Moore J, Mathew S, Raimondi SC, Mukatira ST, Downing JR (March 2003). "TET1, a member of a novel protein family, is fused to MLL in acute myeloid leukemia containing the t(10;11)(q22;q23)". Leukemia. 17 (3): 637–41. doi:10.1038/sj.leu.2402834. PMID12646957.
↑ 11.011.1Neri F, Dettori D, Incarnato D, Krepelova A, Rapelli S, Maldotti M, Parlato C, Paliogiannis P, Oliviero S (August 2015). "TET1 is a tumour suppressor that inhibits colon cancer growth by derepressing inhibitors of the WNT pathway". Oncogene. 34 (32): 4168–76. doi:10.1038/onc.2014.356. PMID25362856.
↑ 13.013.1Hsu CH, Peng KL, Kang ML, Chen YR, Yang YC, Tsai CH, Chu CS, Jeng YM, Chen YT, Lin FM, Huang HD, Lu YY, Teng YC, Lin ST, Lin RK, Tang FM, Lee SB, Hsu HM, Yu JC, Hsiao PW, Juan LJ (September 2012). "TET1 suppresses cancer invasion by activating the tissue inhibitors of metalloproteinases". Cell Reports. 2 (3): 568–79. doi:10.1016/j.celrep.2012.08.030. PMID22999938.
↑ 14.014.1Sang Y, Cheng C, Tang XF, Zhang MF, Lv XB (2015-01-01). "Hypermethylation of TET1 promoter is a new diagnosic marker for breast cancer metastasis". Asian Pacific Journal of Cancer Prevention. 16 (3): 1197–200. doi:10.7314/apjcp.2015.16.3.1197. PMID25735355.
↑Kudo Y, Tateishi K, Yamamoto K, Yamamoto S, Asaoka Y, Ijichi H, Nagae G, Yoshida H, Aburatani H, Koike K (April 2012). "Loss of 5-hydroxymethylcytosine is accompanied with malignant cellular transformation". Cancer Science. 103 (4): 670–6. doi:10.1111/j.1349-7006.2012.02213.x. PMID22320381.
Lorsbach RB, Moore J, Mathew S, Raimondi SC, Mukatira ST, Downing JR (March 2003). "TET1, a member of a novel protein family, is fused to MLL in acute myeloid leukemia containing the t(10;11)(q22;q23)". Leukemia. 17 (3): 637–41. doi:10.1038/sj.leu.2402834. PMID12646957.
Morgan AR, Hamilton G, Turic D, Jehu L, Harold D, Abraham R, Hollingworth P, Moskvina V, Brayne C, Rubinsztein DC, Lynch A, Lawlor B, Gill M, O'Donovan M, Powell J, Lovestone S, Williams J, Owen MJ (September 2008). "Association analysis of 528 intra-genic SNPs in a region of chromosome 10 linked to late onset Alzheimer's disease". American Journal of Medical Genetics Part B. 147B (6): 727–31. doi:10.1002/ajmg.b.30670. PMID18163421.
Ono R, Taki T, Taketani T, Taniwaki M, Kobayashi H, Hayashi Y (July 2002). "LCX, leukemia-associated protein with a CXXC domain, is fused to MLL in acute myeloid leukemia with trilineage dysplasia having t(10;11)(q22;q23)". Cancer Research. 62 (14): 4075–80. PMID12124344.
Mohr F, Döhner K, Buske C, Rawat VP (March 2011). "TET genes: new players in DNA demethylation and important determinants for stemness". Experimental Hematology. 39 (3): 272–81. doi:10.1016/j.exphem.2010.12.004. PMID21168469.