TET1 promotes 5hmC-dependent stemness, and inhibits a 5hmC-independent epithelial-mesenchymal transition, in cervical precancerous lesions

Po Hsuan Su, Yaw Wen Hsu, Rui Lan Huang, Lin Yu Chen, Tai Kuang Chao, Chi Chun Liao, Chien Wen Chen, Tzu I. Wu, Shih Peng Mao, Curt Balch, Hung Cheng Lai

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)53-62
Number of pages10
JournalCancer Letters
Volume450
DOIs
Publication statusPublished - May 28 2019

Fingerprint

Dioxygenases
Epithelial-Mesenchymal Transition
Histones
Gene Silencing
5-Methylcytosine
Neoplasms
DNA
5-hydroxymethylcytosine
1-methylcytosine
Cervix Uteri
Uterine Cervical Neoplasms
Carcinogenesis
Squamous Intraepithelial Lesions of the Cervix

Keywords

  • 5-Hydroxymethylcytosine
  • Cervical cancer
  • DNA demethylation
  • Epithelial-to-mesenchymal transition
  • High-grade squamous intraepithelial lesion (HSIL)
  • Ten-eleven translocation methylcytosine dioxygenase

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

@article{eb1d8865e4d74c67b74e6511bbf6d17f,
title = "TET1 promotes 5hmC-dependent stemness, and inhibits a 5hmC-independent epithelial-mesenchymal transition, in cervical precancerous lesions",
abstract = "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.",
keywords = "5-Hydroxymethylcytosine, Cervical cancer, DNA demethylation, Epithelial-to-mesenchymal transition, High-grade squamous intraepithelial lesion (HSIL), Ten-eleven translocation methylcytosine dioxygenase",
author = "Su, {Po Hsuan} and Hsu, {Yaw Wen} and Huang, {Rui Lan} and Chen, {Lin Yu} and Chao, {Tai Kuang} and Liao, {Chi Chun} and Chen, {Chien Wen} and Wu, {Tzu I.} and Mao, {Shih Peng} and Curt Balch and Lai, {Hung Cheng}",
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doi = "10.1016/j.canlet.2019.01.033",
language = "English",
volume = "450",
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journal = "Cancer Letters",
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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

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

VL - 450

SP - 53

EP - 62

JO - Cancer Letters

JF - Cancer Letters

SN - 0304-3835

ER -