1. ¹Department of Laboratory Medicine and Pathology, Division of Experimental Pathology, Mayo Clinic College of Medicine, Rochester, MN, USA
2. ²Department of Oncology, Division of Medical Oncology, Mayo Clinic College of Medicine, Rochester, MN, USA
3. ³Department of Medicine, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN, USA

Correspondence: Dr V Shridhar, Mayo College of Medicine, 200 First Street, SW, 2-46 Stabile, Rochester, MN 55905, USA. E-mail: shridhar.vijayalakshmi@mayo.edu

⁴These authors contributed equally to this work

Received 9 August 2006; Revised 7 December 2006; Accepted 21 December 2006; Published online 19 February 2007.

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, ² 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.