Promoter hypermethylation of FBXO32, a novel TGF-Β/SMAD4 target gene and tumor suppressor, is associated with poor prognosis in human ovarian cancer

Jian Liang Chou, Her Young Su, Lin Yu Chen, Yu Ping Liao, Corinna Hartman-Frey, Yi Hui Lai, Hui Wen Yang, Daniel E. Deatherage, Chieh Ti Kuo, Yi Wen Huang, Pearlly S. Yan, Shu Huei Hsiao, Chien Kuo Tai, Huey Jen L Lin, Ramana V. Davuluri, Tai Kuang Chao, Kenneth Nephew, Tim H M Huang, Hung Cheng Lai, Michael W Y Chan

Research output: Contribution to journalArticle

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Abstract

Resistance to TGF-Β is frequently observed in ovarian cancer, and disrupted TGF-Β/SMAD4 signaling results in the aberrant expression of downstream target genes in the disease. Our previous study showed that ADAM19, a SMAD4 target gene, is downregulated through epigenetic mechanisms in ovarian cancer with aberrant TGF-Β/SMAD4 signaling. In this study, we investigated the mechanism of downregulation of FBXO32, another SMAD4 target gene, and the clinical significance of the loss of FBXO32 expression in ovarian cancer. Expression of FBXO32 was observed in the normal ovarian surface epithelium, but not in ovarian cancer cell lines. FBXO32 methylation was observed in ovarian cancer cell lines displaying constitutive TGF-Β/SMAD4 signaling, and epigenetic drug treatment restored FBXO32 expression in ovarian cancer cell lines regardless of FBXO32 methylation status, suggesting that epigenetic regulation of this gene in ovarian cancer may be a common event. In advanced-stage ovarian tumors, a significant (29.3%; P0.05) methylation frequency of FBXO32 was observed and the association between FBXO32 methylation and shorter progression-free survival was significant, as determined by both Kaplan-Meier analysis (P0.05) and multivariate Cox regression analysis (hazard ratio: 1.003, P0.05). Reexpression of FBXO32 markedly reduced proliferation of a platinum-resistant ovarian cancer cell line both in vitro and in vivo, due to increased apoptosis of the cells, and resensitized ovarian cancer cells to cisplatin. In conclusion, the novel tumor suppressor FBXO32 is epigenetically silenced in ovarian cancer cell lines with disrupted TGF-Β/SMAD4 signaling, and FBXO32 methylation status predicts survival in patients with ovarian cancer.

Original languageEnglish
Pages (from-to)414-425
Number of pages12
JournalLaboratory Investigation
Volume90
Issue number3
DOIs
StatePublished - Mar 2010

Fingerprint

Tumor Suppressor Genes
Ovarian Neoplasms
Methylation
Cell Line
Epigenomics
Genes
Down-Regulation
Kaplan-Meier Estimate
Platinum
Cisplatin
Disease-Free Survival
Neoplasms
Epithelium
Regression Analysis
Apoptosis
Survival

Keywords

  • Epigenetics
  • FBXO32
  • Ovarian cancer
  • TGF-β

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Cell Biology
  • Molecular Biology

Cite this

Promoter hypermethylation of FBXO32, a novel TGF-Β/SMAD4 target gene and tumor suppressor, is associated with poor prognosis in human ovarian cancer. / Chou, Jian Liang; Su, Her Young; Chen, Lin Yu; Liao, Yu Ping; Hartman-Frey, Corinna; Lai, Yi Hui; Yang, Hui Wen; Deatherage, Daniel E.; Kuo, Chieh Ti; Huang, Yi Wen; Yan, Pearlly S.; Hsiao, Shu Huei; Tai, Chien Kuo; Lin, Huey Jen L; Davuluri, Ramana V.; Chao, Tai Kuang; Nephew, Kenneth; Huang, Tim H M; Lai, Hung Cheng; Chan, Michael W Y.

In: Laboratory Investigation, Vol. 90, No. 3, 03.2010, p. 414-425.

Research output: Contribution to journalArticle

Chou, JL, Su, HY, Chen, LY, Liao, YP, Hartman-Frey, C, Lai, YH, Yang, HW, Deatherage, DE, Kuo, CT, Huang, YW, Yan, PS, Hsiao, SH, Tai, CK, Lin, HJL, Davuluri, RV, Chao, TK, Nephew, K, Huang, THM, Lai, HC & Chan, MWY 2010, 'Promoter hypermethylation of FBXO32, a novel TGF-Β/SMAD4 target gene and tumor suppressor, is associated with poor prognosis in human ovarian cancer', Laboratory Investigation, vol. 90, no. 3, pp. 414-425. https://doi.org/10.1038/labinvest.2009.138
Chou, Jian Liang ; Su, Her Young ; Chen, Lin Yu ; Liao, Yu Ping ; Hartman-Frey, Corinna ; Lai, Yi Hui ; Yang, Hui Wen ; Deatherage, Daniel E. ; Kuo, Chieh Ti ; Huang, Yi Wen ; Yan, Pearlly S. ; Hsiao, Shu Huei ; Tai, Chien Kuo ; Lin, Huey Jen L ; Davuluri, Ramana V. ; Chao, Tai Kuang ; Nephew, Kenneth ; Huang, Tim H M ; Lai, Hung Cheng ; Chan, Michael W Y. / Promoter hypermethylation of FBXO32, a novel TGF-Β/SMAD4 target gene and tumor suppressor, is associated with poor prognosis in human ovarian cancer. In: Laboratory Investigation. 2010 ; Vol. 90, No. 3. pp. 414-425.
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abstract = "Resistance to TGF-Β is frequently observed in ovarian cancer, and disrupted TGF-Β/SMAD4 signaling results in the aberrant expression of downstream target genes in the disease. Our previous study showed that ADAM19, a SMAD4 target gene, is downregulated through epigenetic mechanisms in ovarian cancer with aberrant TGF-Β/SMAD4 signaling. In this study, we investigated the mechanism of downregulation of FBXO32, another SMAD4 target gene, and the clinical significance of the loss of FBXO32 expression in ovarian cancer. Expression of FBXO32 was observed in the normal ovarian surface epithelium, but not in ovarian cancer cell lines. FBXO32 methylation was observed in ovarian cancer cell lines displaying constitutive TGF-Β/SMAD4 signaling, and epigenetic drug treatment restored FBXO32 expression in ovarian cancer cell lines regardless of FBXO32 methylation status, suggesting that epigenetic regulation of this gene in ovarian cancer may be a common event. In advanced-stage ovarian tumors, a significant (29.3{\%}; P0.05) methylation frequency of FBXO32 was observed and the association between FBXO32 methylation and shorter progression-free survival was significant, as determined by both Kaplan-Meier analysis (P0.05) and multivariate Cox regression analysis (hazard ratio: 1.003, P0.05). Reexpression of FBXO32 markedly reduced proliferation of a platinum-resistant ovarian cancer cell line both in vitro and in vivo, due to increased apoptosis of the cells, and resensitized ovarian cancer cells to cisplatin. In conclusion, the novel tumor suppressor FBXO32 is epigenetically silenced in ovarian cancer cell lines with disrupted TGF-Β/SMAD4 signaling, and FBXO32 methylation status predicts survival in patients with ovarian cancer.",
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T1 - Promoter hypermethylation of FBXO32, a novel TGF-Β/SMAD4 target gene and tumor suppressor, is associated with poor prognosis in human ovarian cancer

AU - Chou, Jian Liang

AU - Su, Her Young

AU - Chen, Lin Yu

AU - Liao, Yu Ping

AU - Hartman-Frey, Corinna

AU - Lai, Yi Hui

AU - Yang, Hui Wen

AU - Deatherage, Daniel E.

AU - Kuo, Chieh Ti

AU - Huang, Yi Wen

AU - Yan, Pearlly S.

AU - Hsiao, Shu Huei

AU - Tai, Chien Kuo

AU - Lin, Huey Jen L

AU - Davuluri, Ramana V.

AU - Chao, Tai Kuang

AU - Nephew, Kenneth

AU - Huang, Tim H M

AU - Lai, Hung Cheng

AU - Chan, Michael W Y

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N2 - Resistance to TGF-Β is frequently observed in ovarian cancer, and disrupted TGF-Β/SMAD4 signaling results in the aberrant expression of downstream target genes in the disease. Our previous study showed that ADAM19, a SMAD4 target gene, is downregulated through epigenetic mechanisms in ovarian cancer with aberrant TGF-Β/SMAD4 signaling. In this study, we investigated the mechanism of downregulation of FBXO32, another SMAD4 target gene, and the clinical significance of the loss of FBXO32 expression in ovarian cancer. Expression of FBXO32 was observed in the normal ovarian surface epithelium, but not in ovarian cancer cell lines. FBXO32 methylation was observed in ovarian cancer cell lines displaying constitutive TGF-Β/SMAD4 signaling, and epigenetic drug treatment restored FBXO32 expression in ovarian cancer cell lines regardless of FBXO32 methylation status, suggesting that epigenetic regulation of this gene in ovarian cancer may be a common event. In advanced-stage ovarian tumors, a significant (29.3%; P0.05) methylation frequency of FBXO32 was observed and the association between FBXO32 methylation and shorter progression-free survival was significant, as determined by both Kaplan-Meier analysis (P0.05) and multivariate Cox regression analysis (hazard ratio: 1.003, P0.05). Reexpression of FBXO32 markedly reduced proliferation of a platinum-resistant ovarian cancer cell line both in vitro and in vivo, due to increased apoptosis of the cells, and resensitized ovarian cancer cells to cisplatin. In conclusion, the novel tumor suppressor FBXO32 is epigenetically silenced in ovarian cancer cell lines with disrupted TGF-Β/SMAD4 signaling, and FBXO32 methylation status predicts survival in patients with ovarian cancer.

AB - Resistance to TGF-Β is frequently observed in ovarian cancer, and disrupted TGF-Β/SMAD4 signaling results in the aberrant expression of downstream target genes in the disease. Our previous study showed that ADAM19, a SMAD4 target gene, is downregulated through epigenetic mechanisms in ovarian cancer with aberrant TGF-Β/SMAD4 signaling. In this study, we investigated the mechanism of downregulation of FBXO32, another SMAD4 target gene, and the clinical significance of the loss of FBXO32 expression in ovarian cancer. Expression of FBXO32 was observed in the normal ovarian surface epithelium, but not in ovarian cancer cell lines. FBXO32 methylation was observed in ovarian cancer cell lines displaying constitutive TGF-Β/SMAD4 signaling, and epigenetic drug treatment restored FBXO32 expression in ovarian cancer cell lines regardless of FBXO32 methylation status, suggesting that epigenetic regulation of this gene in ovarian cancer may be a common event. In advanced-stage ovarian tumors, a significant (29.3%; P0.05) methylation frequency of FBXO32 was observed and the association between FBXO32 methylation and shorter progression-free survival was significant, as determined by both Kaplan-Meier analysis (P0.05) and multivariate Cox regression analysis (hazard ratio: 1.003, P0.05). Reexpression of FBXO32 markedly reduced proliferation of a platinum-resistant ovarian cancer cell line both in vitro and in vivo, due to increased apoptosis of the cells, and resensitized ovarian cancer cells to cisplatin. In conclusion, the novel tumor suppressor FBXO32 is epigenetically silenced in ovarian cancer cell lines with disrupted TGF-Β/SMAD4 signaling, and FBXO32 methylation status predicts survival in patients with ovarian cancer.

KW - Epigenetics

KW - FBXO32

KW - Ovarian cancer

KW - TGF-β

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