Repression of IFN regulatory factor 8 by DNA methylation is a molecular determinant of apoptotic resistance and metastatic phenotype in metastatic tumor cells

Dafeng Yang, Muthusamy Thangaraju, Kristy Greeneltch, Darren D. Browning, Patricia V. Schoenlein, Tomohiko Tamura, Keiko Ozato, Vadivel Ganapathy, Scott I. Abrams, Kebin Liu

Research output: Contribution to journalArticle

66 Citations (Scopus)

Abstract

Apoptotic resistance is often associated with metastatic phenotype in tumor cells and is considered a hallmark of tumor progression. In this study, IFN regulatory factor 8 (IRF8) expression was found to be inversely correlated with an apoptotic-resistant and metastatic phenotype in human colon carcinoma cell lines in vitro. This inverse correlation was further extended to spontaneously arising primary mammary carcinoma and lung metastases in a mouse tumor model in vivo. Exogenous expression of IRF8 in the metastatic tumor cell line restored, at least partially, the sensitivity of the tumor cells to Fas-mediated apoptosis, and disruption of IRF8 function conferred the poorly metastatic tumors with enhanced apoptotic resistance and metastatic capability. DNA demethylation restored IRF8 expression and sensitized the metastatic tumor cells to Fas-mediated apoptosis. Analysis of genomic DNA isolated from both primary and metastatic tumor cells with methylation-sensitive PCR revealed hypermethylation of the IRF8 promoter in metastatic tumor cells but not in primary tumor cells. Taken together, our data suggest that IRF8 is both an essential regulator in Fas-mediated apoptosis pathway and a metastasis suppressor in solid tumors and that metastatic tumor cells use DNA hypermethylation to repress IRF8 expression to evade apoptotic cell death and to acquire a metastatic phenotype.

Original languageEnglish (US)
Pages (from-to)3301-3309
Number of pages9
JournalCancer Research
Volume67
Issue number7
DOIs
StatePublished - Apr 1 2007

Fingerprint

DNA Methylation
Phenotype
Neoplasms
Apoptosis
DNA
Neoplasm Metastasis
Tumor Cell Line
Methylation
Colon
Cell Death
Breast Neoplasms
Carcinoma
Cell Line
Polymerase Chain Reaction
Lung

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Repression of IFN regulatory factor 8 by DNA methylation is a molecular determinant of apoptotic resistance and metastatic phenotype in metastatic tumor cells. / Yang, Dafeng; Thangaraju, Muthusamy; Greeneltch, Kristy; Browning, Darren D.; Schoenlein, Patricia V.; Tamura, Tomohiko; Ozato, Keiko; Ganapathy, Vadivel; Abrams, Scott I.; Liu, Kebin.

In: Cancer Research, Vol. 67, No. 7, 01.04.2007, p. 3301-3309.

Research output: Contribution to journalArticle

@article{9c32d7b8d16047ad9ce8db6069b886c5,
title = "Repression of IFN regulatory factor 8 by DNA methylation is a molecular determinant of apoptotic resistance and metastatic phenotype in metastatic tumor cells",
abstract = "Apoptotic resistance is often associated with metastatic phenotype in tumor cells and is considered a hallmark of tumor progression. In this study, IFN regulatory factor 8 (IRF8) expression was found to be inversely correlated with an apoptotic-resistant and metastatic phenotype in human colon carcinoma cell lines in vitro. This inverse correlation was further extended to spontaneously arising primary mammary carcinoma and lung metastases in a mouse tumor model in vivo. Exogenous expression of IRF8 in the metastatic tumor cell line restored, at least partially, the sensitivity of the tumor cells to Fas-mediated apoptosis, and disruption of IRF8 function conferred the poorly metastatic tumors with enhanced apoptotic resistance and metastatic capability. DNA demethylation restored IRF8 expression and sensitized the metastatic tumor cells to Fas-mediated apoptosis. Analysis of genomic DNA isolated from both primary and metastatic tumor cells with methylation-sensitive PCR revealed hypermethylation of the IRF8 promoter in metastatic tumor cells but not in primary tumor cells. Taken together, our data suggest that IRF8 is both an essential regulator in Fas-mediated apoptosis pathway and a metastasis suppressor in solid tumors and that metastatic tumor cells use DNA hypermethylation to repress IRF8 expression to evade apoptotic cell death and to acquire a metastatic phenotype.",
author = "Dafeng Yang and Muthusamy Thangaraju and Kristy Greeneltch and Browning, {Darren D.} and Schoenlein, {Patricia V.} and Tomohiko Tamura and Keiko Ozato and Vadivel Ganapathy and Abrams, {Scott I.} and Kebin Liu",
year = "2007",
month = "4",
day = "1",
doi = "10.1158/0008-5472.CAN-06-4068",
language = "English (US)",
volume = "67",
pages = "3301--3309",
journal = "Cancer Research",
issn = "0008-5472",
publisher = "American Association for Cancer Research Inc.",
number = "7",

}

TY - JOUR

T1 - Repression of IFN regulatory factor 8 by DNA methylation is a molecular determinant of apoptotic resistance and metastatic phenotype in metastatic tumor cells

AU - Yang, Dafeng

AU - Thangaraju, Muthusamy

AU - Greeneltch, Kristy

AU - Browning, Darren D.

AU - Schoenlein, Patricia V.

AU - Tamura, Tomohiko

AU - Ozato, Keiko

AU - Ganapathy, Vadivel

AU - Abrams, Scott I.

AU - Liu, Kebin

PY - 2007/4/1

Y1 - 2007/4/1

N2 - Apoptotic resistance is often associated with metastatic phenotype in tumor cells and is considered a hallmark of tumor progression. In this study, IFN regulatory factor 8 (IRF8) expression was found to be inversely correlated with an apoptotic-resistant and metastatic phenotype in human colon carcinoma cell lines in vitro. This inverse correlation was further extended to spontaneously arising primary mammary carcinoma and lung metastases in a mouse tumor model in vivo. Exogenous expression of IRF8 in the metastatic tumor cell line restored, at least partially, the sensitivity of the tumor cells to Fas-mediated apoptosis, and disruption of IRF8 function conferred the poorly metastatic tumors with enhanced apoptotic resistance and metastatic capability. DNA demethylation restored IRF8 expression and sensitized the metastatic tumor cells to Fas-mediated apoptosis. Analysis of genomic DNA isolated from both primary and metastatic tumor cells with methylation-sensitive PCR revealed hypermethylation of the IRF8 promoter in metastatic tumor cells but not in primary tumor cells. Taken together, our data suggest that IRF8 is both an essential regulator in Fas-mediated apoptosis pathway and a metastasis suppressor in solid tumors and that metastatic tumor cells use DNA hypermethylation to repress IRF8 expression to evade apoptotic cell death and to acquire a metastatic phenotype.

AB - Apoptotic resistance is often associated with metastatic phenotype in tumor cells and is considered a hallmark of tumor progression. In this study, IFN regulatory factor 8 (IRF8) expression was found to be inversely correlated with an apoptotic-resistant and metastatic phenotype in human colon carcinoma cell lines in vitro. This inverse correlation was further extended to spontaneously arising primary mammary carcinoma and lung metastases in a mouse tumor model in vivo. Exogenous expression of IRF8 in the metastatic tumor cell line restored, at least partially, the sensitivity of the tumor cells to Fas-mediated apoptosis, and disruption of IRF8 function conferred the poorly metastatic tumors with enhanced apoptotic resistance and metastatic capability. DNA demethylation restored IRF8 expression and sensitized the metastatic tumor cells to Fas-mediated apoptosis. Analysis of genomic DNA isolated from both primary and metastatic tumor cells with methylation-sensitive PCR revealed hypermethylation of the IRF8 promoter in metastatic tumor cells but not in primary tumor cells. Taken together, our data suggest that IRF8 is both an essential regulator in Fas-mediated apoptosis pathway and a metastasis suppressor in solid tumors and that metastatic tumor cells use DNA hypermethylation to repress IRF8 expression to evade apoptotic cell death and to acquire a metastatic phenotype.

UR - http://www.scopus.com/inward/record.url?scp=34248230089&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34248230089&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-06-4068

DO - 10.1158/0008-5472.CAN-06-4068

M3 - Article

C2 - 17409439

AN - SCOPUS:34248230089

VL - 67

SP - 3301

EP - 3309

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 7

ER -