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

Oncogene volume 26, pages 4969–4978 (2007)Cite this article

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.

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Acknowledgements

This work was supported by grants from the US National Cancer Institute (CA106954-02), the John W Anderson Foundation, Minnesota Ovarian Cancer Alliance (MOCA), Edith and Bernard Waterman Foundation and the Mayo Foundation (all to VS). We would like to acknowledge Dr Lynn Hartmann and Dr Kimberly Kalli for providing us with the ovarian tissue microarray.

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  1. J Staub, J Chien and V Shridhar: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Laboratory Medicine and Pathology, Division of Experimental Pathology, Mayo Clinic College of Medicine, Rochester, MN, USA

    J Staub, J Chien, Y Pan, X Qian, K Narita, G Aletti & V Shridhar

  2. Department of Oncology, Division of Medical Oncology, Mayo Clinic College of Medicine, Rochester, MN, USA

    M Scheerer & J Molina

  3. Department of Medicine, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN, USA

    L R Roberts

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Correspondence to V Shridhar.

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Staub, J., Chien, J., Pan, Y. et al. Epigenetic silencing of HSulf-1 in ovarian cancer:implications in chemoresistance. Oncogene 26, 4969–4978 (2007). https://doi.org/10.1038/sj.onc.1210300

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