TY - JOUR
T1 - TET1 promotes 5hmC-dependent stemness, and inhibits a 5hmC-independent epithelial-mesenchymal transition, in cervical precancerous lesions
AU - Su, Po Hsuan
AU - Hsu, Yaw Wen
AU - Huang, Rui Lan
AU - Chen, Lin Yu
AU - Chao, Tai Kuang
AU - Liao, Chi Chun
AU - Chen, Chien Wen
AU - Wu, Tzu I.
AU - Mao, Shih Peng
AU - Balch, Curt
AU - Lai, Hung Cheng
N1 - Copyright © 2019 Elsevier B.V. All rights reserved.
PY - 2019/5/28
Y1 - 2019/5/28
N2 - DNA hypermethylation is a driving force in carcinogenesis. However, the role of active DNA hypomethylation in cancer remains largely unknown. This process, facilitated by ten-eleven translocation methylcytosine dioxygenase 1 (TET1), which oxidizes 5-methylcytosine (5 mC) to 5-hydroxymethylcytosine (5hmC), has never been studied in cervical cancer. Here, we found that TET1 and 5hmC correlative increases from normal cervix to Low-grade squamous intraepithelial lesion (LSIL), maximizing in High-grade squamous intraepithelial lesion (HSIL), and decreasing in invasive cancer. Full-length HPV-immortalized HSIL cells demonstrated higher TET1/5hmC levels, and stemness properties, compared to invasive cancer cells. TET1 silencing promoted the epithelial-mesenchymal transition (EMT), to transform precancerous cells in vivo. TET1 increased 5hmC in the ZEB1 and VIM promoters, surprisingly, silencing both genes. TET1 interaction with the histone modifiers, LSD1 and EZH2, on the ZEB1 promoter, resulted in gene silencing, via loss of histone H3K4 trimethylation, and gain of histone H3K27 trimethylation. Taken together, TET1 promotes stemness properties, and inhibits EMT, in HSIL cells, through 5hmC-dependent and -independent mechanisms.
AB - DNA hypermethylation is a driving force in carcinogenesis. However, the role of active DNA hypomethylation in cancer remains largely unknown. This process, facilitated by ten-eleven translocation methylcytosine dioxygenase 1 (TET1), which oxidizes 5-methylcytosine (5 mC) to 5-hydroxymethylcytosine (5hmC), has never been studied in cervical cancer. Here, we found that TET1 and 5hmC correlative increases from normal cervix to Low-grade squamous intraepithelial lesion (LSIL), maximizing in High-grade squamous intraepithelial lesion (HSIL), and decreasing in invasive cancer. Full-length HPV-immortalized HSIL cells demonstrated higher TET1/5hmC levels, and stemness properties, compared to invasive cancer cells. TET1 silencing promoted the epithelial-mesenchymal transition (EMT), to transform precancerous cells in vivo. TET1 increased 5hmC in the ZEB1 and VIM promoters, surprisingly, silencing both genes. TET1 interaction with the histone modifiers, LSD1 and EZH2, on the ZEB1 promoter, resulted in gene silencing, via loss of histone H3K4 trimethylation, and gain of histone H3K27 trimethylation. Taken together, TET1 promotes stemness properties, and inhibits EMT, in HSIL cells, through 5hmC-dependent and -independent mechanisms.
KW - 5-Hydroxymethylcytosine
KW - Cervical cancer
KW - DNA demethylation
KW - Epithelial-to-mesenchymal transition
KW - High-grade squamous intraepithelial lesion (HSIL)
KW - Ten-eleven translocation methylcytosine dioxygenase
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U2 - 10.1016/j.canlet.2019.01.033
DO - 10.1016/j.canlet.2019.01.033
M3 - Article
C2 - 30771438
AN - SCOPUS:85062207349
SN - 0304-3835
VL - 450
SP - 53
EP - 62
JO - Cancer Letters
JF - Cancer Letters
ER -