Epigenetic silencing of HSulf-1 in ovarian cancer: Implications in chemoresistance

J. Staub, J. Chien, Y. Pan, X. Qian, K. Narita, G. Aletti, M. Scheerer, Lewis Rowland Roberts, Julian R Molina, Vijayalakshmi Shridhar

Research output: Contribution to journalArticle

75 Citations (Scopus)

Abstract

To investigate the mechanism by which HSulf-1 expression is downregulated in ovarian cancer, DNA methylation and histone acetylation of HSulf-1 was analysed in ovarian cancer cell lines and primary tumors. Treatment of OV207 and SKOV3 by 5-aza-2′-deoxycytidine resulted in increased transcription of HSulf-1. Sequence analysis of bisulfite-modified genomic DNA from ovarian cell lines and primary tumors without HSulf-1 expression revealed an increase in the frequency of methylation of 12 CpG sites in exon 1A. Chromatin immunoprecipitation assays showed an increase in histone H3 methylation in cell lines without HSulf-1 expression. To assess the significance of HSulf-1 downregulation in ovarian cancer, OV167 and OV202 cells were transfected with HSulf-1 siRNA. Downregulation of HSulf-1 expression in OV167 and OV202 cells lead to an attenuation of cisplatin-induced cytotoxicity. Moreover, patients with ovarian tumors expressing higher levels of HSulf-1 showed a 90% response rate (27/30) to chemotherapy compared to a response rate of 63% (19/30) in those with weak or moderate levels (P=0.0146, χ2 test). Collectively, these data indicate that HSulf-1 is epigenetically silenced in ovarian cancer and that epigenetic therapy targeting HSulf-1 might sensitize ovarian tumors to conventional first-line therapies.

Original languageEnglish (US)
Pages (from-to)4969-4978
Number of pages10
JournalOncogene
Volume26
Issue number34
DOIs
StatePublished - Jul 26 2007

Fingerprint

Epigenomics
Ovarian Neoplasms
Down-Regulation
decitabine
Tumor Cell Line
Histones
Methylation
Chromatin Immunoprecipitation
DNA Methylation
Acetylation
Small Interfering RNA
Cisplatin
Sequence Analysis
Exons
Neoplasms
Therapeutics
Drug Therapy
Cell Line
DNA

Keywords

  • Apoptosis
  • Chemoresponse
  • Histone modification
  • Methylation
  • Tumor suppressor

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Epigenetic silencing of HSulf-1 in ovarian cancer : Implications in chemoresistance. / Staub, J.; Chien, J.; Pan, Y.; Qian, X.; Narita, K.; Aletti, G.; Scheerer, M.; Roberts, Lewis Rowland; Molina, Julian R; Shridhar, Vijayalakshmi.

In: Oncogene, Vol. 26, No. 34, 26.07.2007, p. 4969-4978.

Research output: Contribution to journalArticle

Staub, J, Chien, J, Pan, Y, Qian, X, Narita, K, Aletti, G, Scheerer, M, Roberts, LR, Molina, JR & Shridhar, V 2007, 'Epigenetic silencing of HSulf-1 in ovarian cancer: Implications in chemoresistance', Oncogene, vol. 26, no. 34, pp. 4969-4978. https://doi.org/10.1038/sj.onc.1210300
Staub J, Chien J, Pan Y, Qian X, Narita K, Aletti G et al. Epigenetic silencing of HSulf-1 in ovarian cancer: Implications in chemoresistance. Oncogene. 2007 Jul 26;26(34):4969-4978. https://doi.org/10.1038/sj.onc.1210300
Staub, J. ; Chien, J. ; Pan, Y. ; Qian, X. ; Narita, K. ; Aletti, G. ; Scheerer, M. ; Roberts, Lewis Rowland ; Molina, Julian R ; Shridhar, Vijayalakshmi. / Epigenetic silencing of HSulf-1 in ovarian cancer : Implications in chemoresistance. In: Oncogene. 2007 ; Vol. 26, No. 34. pp. 4969-4978.
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