Functional Switching of TGF-β1 Signaling in Liver Cancer via Epigenetic Modulation of a Single CpG Site in TTP Promoter

Bo Hwa Sohn; In Young Park; Jung Ju Lee; Suk Jin Yang; Ye Jin Jang; Kyung Chan Park; Dong Joon Kim; Dong Chul Lee; Hyun Ahm Sohn; Tae Woo Kim; Hyang Sook Yoo; Jong Young Choi; Yun Soo Bae; Young Il Yeom

doi:10.1053/j.gastro.2009.12.044

Functional Switching of TGF-β1 Signaling in Liver Cancer via Epigenetic Modulation of a Single CpG Site in TTP Promoter

Bo Hwa Sohn, In Young Park, Jung Ju Lee, Suk Jin Yang, Ye Jin Jang, Kyung Chan Park, Dong Joon Kim, Dong Chul Lee, Hyun Ahm Sohn, Tae Woo Kim, Hyang Sook Yoo, Jong Young Choi, Yun Soo Bae, Young Il Yeom

Department of Life Science

Research output: Contribution to journal › Article › peer-review

89 Scopus citations

Abstract

Background & Aims: Acquisition of resistance to the antiproliferative effect of transforming growth factor (TGF)-β1 is crucial for the malignant progression of cancers. In this study, we sought to determine whether deregulated expression of tristetrapolin (TTP), a negative posttranscriptional regulator of c-Myc, confers resistance to the antiproliferative effects of TGF-β1 on liver cancer cells. Methods: The epigenetics of TTP promoter regulation and its effects on TGF-β1 signaling were examined in hepatocellular carcinoma (HCC) cell lines and patient tissues. Results: TTP was down-regulated in HCC cell lines (10/11), compared with normal liver, as well as in tumor tissues (19/24) from paired HCC specimens. Methylation of a specific single CpG site located within the TGF-β1-responsive region (TRR) of the TTP promoter was significantly associated with TTP down-regulation in both HCC cell lines and tumor tissues (r = -0.606383, P < .001). The singly methylated CpG site was specifically bound by a transcriptional repressor complex consisting of MECP2/c-Ski/DNMT3A and abolished the TGF-β1-induced as well as basal-level expression of TTP. The epigenetic inactivation of TTP led to an increased half-life of c-Myc mRNA and blocked the cytostatic effect of TGF-β1. Statistically significant correlations were observed between the single CpG site methylation and expression levels of TTP or c-Myc in clinical samples of HCC. Conclusions: Abrogation of the post-transcriptional regulation of c-Myc via methylation of a specific single CpG site in the TTP promoter presents a novel mechanism for the gain of selective resistance to the antiproliferative signaling of TGF-β1 in HCC.

Original language	English
Pages (from-to)	1898-1908.e12
Journal	Gastroenterology
Volume	138
Issue number	5
DOIs	https://doi.org/10.1053/j.gastro.2009.12.044
State	Published - May 2010

Bibliographical note

Funding Information:
Funding Supported by grants from the 21C Frontier Human Genome Functional Analysis Project and the Korean Systems Biology Research Program of the Ministry of Science and Technology of Korea and the KRIBB Research Initiative Program .

Keywords

HCC
Methylation
TGF-β1
TTP

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1053/j.gastro.2009.12.044

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Sohn, B. H., Park, I. Y., Lee, J. J., Yang, S. J., Jang, Y. J., Park, K. C., Kim, D. J., Lee, D. C., Sohn, H. A., Kim, T. W., Yoo, H. S., Choi, J. Y., Bae, Y. S., & Yeom, Y. I. (2010). Functional Switching of TGF-β1 Signaling in Liver Cancer via Epigenetic Modulation of a Single CpG Site in TTP Promoter. Gastroenterology, 138(5), 1898-1908.e12. https://doi.org/10.1053/j.gastro.2009.12.044

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title = "Functional Switching of TGF-β1 Signaling in Liver Cancer via Epigenetic Modulation of a Single CpG Site in TTP Promoter",

abstract = "Background & Aims: Acquisition of resistance to the antiproliferative effect of transforming growth factor (TGF)-β1 is crucial for the malignant progression of cancers. In this study, we sought to determine whether deregulated expression of tristetrapolin (TTP), a negative posttranscriptional regulator of c-Myc, confers resistance to the antiproliferative effects of TGF-β1 on liver cancer cells. Methods: The epigenetics of TTP promoter regulation and its effects on TGF-β1 signaling were examined in hepatocellular carcinoma (HCC) cell lines and patient tissues. Results: TTP was down-regulated in HCC cell lines (10/11), compared with normal liver, as well as in tumor tissues (19/24) from paired HCC specimens. Methylation of a specific single CpG site located within the TGF-β1-responsive region (TRR) of the TTP promoter was significantly associated with TTP down-regulation in both HCC cell lines and tumor tissues (r = -0.606383, P < .001). The singly methylated CpG site was specifically bound by a transcriptional repressor complex consisting of MECP2/c-Ski/DNMT3A and abolished the TGF-β1-induced as well as basal-level expression of TTP. The epigenetic inactivation of TTP led to an increased half-life of c-Myc mRNA and blocked the cytostatic effect of TGF-β1. Statistically significant correlations were observed between the single CpG site methylation and expression levels of TTP or c-Myc in clinical samples of HCC. Conclusions: Abrogation of the post-transcriptional regulation of c-Myc via methylation of a specific single CpG site in the TTP promoter presents a novel mechanism for the gain of selective resistance to the antiproliferative signaling of TGF-β1 in HCC.",

keywords = "HCC, Methylation, TGF-β1, TTP",

author = "Sohn, {Bo Hwa} and Park, {In Young} and Lee, {Jung Ju} and Yang, {Suk Jin} and Jang, {Ye Jin} and Park, {Kyung Chan} and Kim, {Dong Joon} and Lee, {Dong Chul} and Sohn, {Hyun Ahm} and Kim, {Tae Woo} and Yoo, {Hyang Sook} and Choi, {Jong Young} and Bae, {Yun Soo} and Yeom, {Young Il}",

note = "Funding Information: Funding Supported by grants from the 21C Frontier Human Genome Functional Analysis Project and the Korean Systems Biology Research Program of the Ministry of Science and Technology of Korea and the KRIBB Research Initiative Program . ",

year = "2010",

month = may,

doi = "10.1053/j.gastro.2009.12.044",

language = "English",

volume = "138",

pages = "1898--1908.e12",

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T1 - Functional Switching of TGF-β1 Signaling in Liver Cancer via Epigenetic Modulation of a Single CpG Site in TTP Promoter

AU - Sohn, Bo Hwa

AU - Park, In Young

AU - Lee, Jung Ju

AU - Yang, Suk Jin

AU - Jang, Ye Jin

AU - Park, Kyung Chan

AU - Kim, Dong Joon

AU - Lee, Dong Chul

AU - Sohn, Hyun Ahm

AU - Kim, Tae Woo

AU - Yoo, Hyang Sook

AU - Choi, Jong Young

AU - Bae, Yun Soo

AU - Yeom, Young Il

N1 - Funding Information: Funding Supported by grants from the 21C Frontier Human Genome Functional Analysis Project and the Korean Systems Biology Research Program of the Ministry of Science and Technology of Korea and the KRIBB Research Initiative Program .

PY - 2010/5

Y1 - 2010/5

N2 - Background & Aims: Acquisition of resistance to the antiproliferative effect of transforming growth factor (TGF)-β1 is crucial for the malignant progression of cancers. In this study, we sought to determine whether deregulated expression of tristetrapolin (TTP), a negative posttranscriptional regulator of c-Myc, confers resistance to the antiproliferative effects of TGF-β1 on liver cancer cells. Methods: The epigenetics of TTP promoter regulation and its effects on TGF-β1 signaling were examined in hepatocellular carcinoma (HCC) cell lines and patient tissues. Results: TTP was down-regulated in HCC cell lines (10/11), compared with normal liver, as well as in tumor tissues (19/24) from paired HCC specimens. Methylation of a specific single CpG site located within the TGF-β1-responsive region (TRR) of the TTP promoter was significantly associated with TTP down-regulation in both HCC cell lines and tumor tissues (r = -0.606383, P < .001). The singly methylated CpG site was specifically bound by a transcriptional repressor complex consisting of MECP2/c-Ski/DNMT3A and abolished the TGF-β1-induced as well as basal-level expression of TTP. The epigenetic inactivation of TTP led to an increased half-life of c-Myc mRNA and blocked the cytostatic effect of TGF-β1. Statistically significant correlations were observed between the single CpG site methylation and expression levels of TTP or c-Myc in clinical samples of HCC. Conclusions: Abrogation of the post-transcriptional regulation of c-Myc via methylation of a specific single CpG site in the TTP promoter presents a novel mechanism for the gain of selective resistance to the antiproliferative signaling of TGF-β1 in HCC.

AB - Background & Aims: Acquisition of resistance to the antiproliferative effect of transforming growth factor (TGF)-β1 is crucial for the malignant progression of cancers. In this study, we sought to determine whether deregulated expression of tristetrapolin (TTP), a negative posttranscriptional regulator of c-Myc, confers resistance to the antiproliferative effects of TGF-β1 on liver cancer cells. Methods: The epigenetics of TTP promoter regulation and its effects on TGF-β1 signaling were examined in hepatocellular carcinoma (HCC) cell lines and patient tissues. Results: TTP was down-regulated in HCC cell lines (10/11), compared with normal liver, as well as in tumor tissues (19/24) from paired HCC specimens. Methylation of a specific single CpG site located within the TGF-β1-responsive region (TRR) of the TTP promoter was significantly associated with TTP down-regulation in both HCC cell lines and tumor tissues (r = -0.606383, P < .001). The singly methylated CpG site was specifically bound by a transcriptional repressor complex consisting of MECP2/c-Ski/DNMT3A and abolished the TGF-β1-induced as well as basal-level expression of TTP. The epigenetic inactivation of TTP led to an increased half-life of c-Myc mRNA and blocked the cytostatic effect of TGF-β1. Statistically significant correlations were observed between the single CpG site methylation and expression levels of TTP or c-Myc in clinical samples of HCC. Conclusions: Abrogation of the post-transcriptional regulation of c-Myc via methylation of a specific single CpG site in the TTP promoter presents a novel mechanism for the gain of selective resistance to the antiproliferative signaling of TGF-β1 in HCC.

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Functional Switching of TGF-β1 Signaling in Liver Cancer via Epigenetic Modulation of a Single CpG Site in TTP Promoter

Abstract

Bibliographical note

Keywords

UN SDGs

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