Hypermethylation of the tgf-β target, abca1 is associated with poor prognosis in ovarian cancer patients

Jian Liang Chou, Rui Lan Huang, Jacqueline Shay, Lin Yu Chen, Sheng Jie Lin, Pearlly S. Yan, Wei Ting Chao, Yi Hui Lai, Yen Ling Lai, Tai Kuang Chao, Cheng I. Lee, Chien Kuo Tai, Shu Fen Wu, Kenneth Nephew, Tim H M Huang, Hung Cheng Lai, Michael W Y Chan

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Background: The dysregulation of transforming growth factor-β (TGF-β) signaling plays a crucial role in ovarian carcinogenesis and in maintaining cancer stem cell properties. Classified as a member of the ATP-binding cassette (ABC) family, ABCA1 was previously identified by methylated DNA immunoprecipitation microarray (mDIP-Chip) to be methylated in ovarian cancer cell lines, A2780 and CP70. By microarray, it was also found to be upregulated in immortalized ovarian surface epithelial (IOSE) cells following TGF-β treatment. Thus, we hypothesized that ABCA1 may be involved in ovarian cancer and its initiation. Results: We first compared the expression level of ABCA1 in IOSE cells and a panel of ovarian cancer cell lines and found that ABCA1 was expressed in HeyC2, SKOV3, MCP3, and MCP2 ovarian cancer cell lines but downregulated in A2780 and CP70 ovarian cancer cell lines. The reduced expression of ABCA1 in A2780 and CP70 cells was associated with promoter hypermethylation, as demonstrated by bisulfite pyro-sequencing. We also found that knockdown of ABCA1 increased the cholesterol level and promoted cell growth in vitro and in vivo. Further analysis of ABCA1 methylation in 76 ovarian cancer patient samples demonstrated that patients with higher ABCA1 methylation are associated with high stage (P = 0.0131) and grade (P = 0.0137). Kaplan-Meier analysis also found that patients with higher levels of methylation of ABCA1 have shorter overall survival (P = 0.019). Furthermore, tissue microarray using 55 ovarian cancer patient samples revealed that patients with a lower level of ABCA1 expression are associated with shorter progress-free survival (P = 0.038). Conclusions: ABCA1 may be a tumor suppressor and is hypermethylated in a subset of ovarian cancer patients. Hypermethylation of ABCA1 is associated with poor prognosis in these patients.

Original languageEnglish
JournalClinical Epigenetics
Volume7
Issue number1
DOIs
StatePublished - Jan 14 2015

Fingerprint

Ovarian Neoplasms
Methylation
Cell Line
Transforming Growth Factors
Epithelial Cells
Survival
Neoplastic Stem Cells
Kaplan-Meier Estimate
Oligonucleotide Array Sequence Analysis
Immunoprecipitation
Carcinogenesis
Down-Regulation
Adenosine Triphosphate
Cholesterol
Growth
Neoplasms

Keywords

  • ABCA1
  • Epigenetics
  • Ovarian cancer

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Developmental Biology
  • Genetics(clinical)

Cite this

Chou, J. L., Huang, R. L., Shay, J., Chen, L. Y., Lin, S. J., Yan, P. S., ... Chan, M. W. Y. (2015). Hypermethylation of the tgf-β target, abca1 is associated with poor prognosis in ovarian cancer patients. Clinical Epigenetics, 7(1). https://doi.org/10.1186/s13148-014-0036-2

Hypermethylation of the tgf-β target, abca1 is associated with poor prognosis in ovarian cancer patients. / Chou, Jian Liang; Huang, Rui Lan; Shay, Jacqueline; Chen, Lin Yu; Lin, Sheng Jie; Yan, Pearlly S.; Chao, Wei Ting; Lai, Yi Hui; Lai, Yen Ling; Chao, Tai Kuang; Lee, Cheng I.; Tai, Chien Kuo; Wu, Shu Fen; Nephew, Kenneth; Huang, Tim H M; Lai, Hung Cheng; Chan, Michael W Y.

In: Clinical Epigenetics, Vol. 7, No. 1, 14.01.2015.

Research output: Contribution to journalArticle

Chou, JL, Huang, RL, Shay, J, Chen, LY, Lin, SJ, Yan, PS, Chao, WT, Lai, YH, Lai, YL, Chao, TK, Lee, CI, Tai, CK, Wu, SF, Nephew, K, Huang, THM, Lai, HC & Chan, MWY 2015, 'Hypermethylation of the tgf-β target, abca1 is associated with poor prognosis in ovarian cancer patients', Clinical Epigenetics, vol. 7, no. 1. https://doi.org/10.1186/s13148-014-0036-2
Chou, Jian Liang ; Huang, Rui Lan ; Shay, Jacqueline ; Chen, Lin Yu ; Lin, Sheng Jie ; Yan, Pearlly S. ; Chao, Wei Ting ; Lai, Yi Hui ; Lai, Yen Ling ; Chao, Tai Kuang ; Lee, Cheng I. ; Tai, Chien Kuo ; Wu, Shu Fen ; Nephew, Kenneth ; Huang, Tim H M ; Lai, Hung Cheng ; Chan, Michael W Y. / Hypermethylation of the tgf-β target, abca1 is associated with poor prognosis in ovarian cancer patients. In: Clinical Epigenetics. 2015 ; Vol. 7, No. 1.
@article{92ff9c7b300b4d15b7529ad6c5b479cd,
title = "Hypermethylation of the tgf-β target, abca1 is associated with poor prognosis in ovarian cancer patients",
abstract = "Background: The dysregulation of transforming growth factor-β (TGF-β) signaling plays a crucial role in ovarian carcinogenesis and in maintaining cancer stem cell properties. Classified as a member of the ATP-binding cassette (ABC) family, ABCA1 was previously identified by methylated DNA immunoprecipitation microarray (mDIP-Chip) to be methylated in ovarian cancer cell lines, A2780 and CP70. By microarray, it was also found to be upregulated in immortalized ovarian surface epithelial (IOSE) cells following TGF-β treatment. Thus, we hypothesized that ABCA1 may be involved in ovarian cancer and its initiation. Results: We first compared the expression level of ABCA1 in IOSE cells and a panel of ovarian cancer cell lines and found that ABCA1 was expressed in HeyC2, SKOV3, MCP3, and MCP2 ovarian cancer cell lines but downregulated in A2780 and CP70 ovarian cancer cell lines. The reduced expression of ABCA1 in A2780 and CP70 cells was associated with promoter hypermethylation, as demonstrated by bisulfite pyro-sequencing. We also found that knockdown of ABCA1 increased the cholesterol level and promoted cell growth in vitro and in vivo. Further analysis of ABCA1 methylation in 76 ovarian cancer patient samples demonstrated that patients with higher ABCA1 methylation are associated with high stage (P = 0.0131) and grade (P = 0.0137). Kaplan-Meier analysis also found that patients with higher levels of methylation of ABCA1 have shorter overall survival (P = 0.019). Furthermore, tissue microarray using 55 ovarian cancer patient samples revealed that patients with a lower level of ABCA1 expression are associated with shorter progress-free survival (P = 0.038). Conclusions: ABCA1 may be a tumor suppressor and is hypermethylated in a subset of ovarian cancer patients. Hypermethylation of ABCA1 is associated with poor prognosis in these patients.",
keywords = "ABCA1, Epigenetics, Ovarian cancer",
author = "Chou, {Jian Liang} and Huang, {Rui Lan} and Jacqueline Shay and Chen, {Lin Yu} and Lin, {Sheng Jie} and Yan, {Pearlly S.} and Chao, {Wei Ting} and Lai, {Yi Hui} and Lai, {Yen Ling} and Chao, {Tai Kuang} and Lee, {Cheng I.} and Tai, {Chien Kuo} and Wu, {Shu Fen} and Kenneth Nephew and Huang, {Tim H M} and Lai, {Hung Cheng} and Chan, {Michael W Y}",
year = "2015",
month = "1",
day = "14",
doi = "10.1186/s13148-014-0036-2",
language = "English",
volume = "7",
journal = "Clinical Epigenetics",
issn = "1868-7075",
publisher = "Springer Verlag",
number = "1",

}

TY - JOUR

T1 - Hypermethylation of the tgf-β target, abca1 is associated with poor prognosis in ovarian cancer patients

AU - Chou, Jian Liang

AU - Huang, Rui Lan

AU - Shay, Jacqueline

AU - Chen, Lin Yu

AU - Lin, Sheng Jie

AU - Yan, Pearlly S.

AU - Chao, Wei Ting

AU - Lai, Yi Hui

AU - Lai, Yen Ling

AU - Chao, Tai Kuang

AU - Lee, Cheng I.

AU - Tai, Chien Kuo

AU - Wu, Shu Fen

AU - Nephew, Kenneth

AU - Huang, Tim H M

AU - Lai, Hung Cheng

AU - Chan, Michael W Y

PY - 2015/1/14

Y1 - 2015/1/14

N2 - Background: The dysregulation of transforming growth factor-β (TGF-β) signaling plays a crucial role in ovarian carcinogenesis and in maintaining cancer stem cell properties. Classified as a member of the ATP-binding cassette (ABC) family, ABCA1 was previously identified by methylated DNA immunoprecipitation microarray (mDIP-Chip) to be methylated in ovarian cancer cell lines, A2780 and CP70. By microarray, it was also found to be upregulated in immortalized ovarian surface epithelial (IOSE) cells following TGF-β treatment. Thus, we hypothesized that ABCA1 may be involved in ovarian cancer and its initiation. Results: We first compared the expression level of ABCA1 in IOSE cells and a panel of ovarian cancer cell lines and found that ABCA1 was expressed in HeyC2, SKOV3, MCP3, and MCP2 ovarian cancer cell lines but downregulated in A2780 and CP70 ovarian cancer cell lines. The reduced expression of ABCA1 in A2780 and CP70 cells was associated with promoter hypermethylation, as demonstrated by bisulfite pyro-sequencing. We also found that knockdown of ABCA1 increased the cholesterol level and promoted cell growth in vitro and in vivo. Further analysis of ABCA1 methylation in 76 ovarian cancer patient samples demonstrated that patients with higher ABCA1 methylation are associated with high stage (P = 0.0131) and grade (P = 0.0137). Kaplan-Meier analysis also found that patients with higher levels of methylation of ABCA1 have shorter overall survival (P = 0.019). Furthermore, tissue microarray using 55 ovarian cancer patient samples revealed that patients with a lower level of ABCA1 expression are associated with shorter progress-free survival (P = 0.038). Conclusions: ABCA1 may be a tumor suppressor and is hypermethylated in a subset of ovarian cancer patients. Hypermethylation of ABCA1 is associated with poor prognosis in these patients.

AB - Background: The dysregulation of transforming growth factor-β (TGF-β) signaling plays a crucial role in ovarian carcinogenesis and in maintaining cancer stem cell properties. Classified as a member of the ATP-binding cassette (ABC) family, ABCA1 was previously identified by methylated DNA immunoprecipitation microarray (mDIP-Chip) to be methylated in ovarian cancer cell lines, A2780 and CP70. By microarray, it was also found to be upregulated in immortalized ovarian surface epithelial (IOSE) cells following TGF-β treatment. Thus, we hypothesized that ABCA1 may be involved in ovarian cancer and its initiation. Results: We first compared the expression level of ABCA1 in IOSE cells and a panel of ovarian cancer cell lines and found that ABCA1 was expressed in HeyC2, SKOV3, MCP3, and MCP2 ovarian cancer cell lines but downregulated in A2780 and CP70 ovarian cancer cell lines. The reduced expression of ABCA1 in A2780 and CP70 cells was associated with promoter hypermethylation, as demonstrated by bisulfite pyro-sequencing. We also found that knockdown of ABCA1 increased the cholesterol level and promoted cell growth in vitro and in vivo. Further analysis of ABCA1 methylation in 76 ovarian cancer patient samples demonstrated that patients with higher ABCA1 methylation are associated with high stage (P = 0.0131) and grade (P = 0.0137). Kaplan-Meier analysis also found that patients with higher levels of methylation of ABCA1 have shorter overall survival (P = 0.019). Furthermore, tissue microarray using 55 ovarian cancer patient samples revealed that patients with a lower level of ABCA1 expression are associated with shorter progress-free survival (P = 0.038). Conclusions: ABCA1 may be a tumor suppressor and is hypermethylated in a subset of ovarian cancer patients. Hypermethylation of ABCA1 is associated with poor prognosis in these patients.

KW - ABCA1

KW - Epigenetics

KW - Ovarian cancer

UR - http://www.scopus.com/inward/record.url?scp=84927145245&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84927145245&partnerID=8YFLogxK

U2 - 10.1186/s13148-014-0036-2

DO - 10.1186/s13148-014-0036-2

M3 - Article

AN - SCOPUS:84927145245

VL - 7

JO - Clinical Epigenetics

JF - Clinical Epigenetics

SN - 1868-7075

IS - 1

ER -