Secreted frizzled-related protein-5 is epigenetically downregulated and functions as a tumor suppressor in kidney cancer

Kazumori Kawakami, Soichiro Yamamura, Hiroshi Hirata, Koji Ueno, Sharanjot Saini, Shahana Majid, Yuichiro Tanaka, Ken Kawamoto, Hideki Enokida, Masayuki Nakagawa, Rajvir Dahiya

Research output: Contribution to journalArticle

38 Scopus citations

Abstract

Secreted frizzled-related protein-5 (sFRP-5) has been identified as 1 of the secreted antagonists that bind Wnt protein. However, the functional significance of sFRP-5 in renal cell cancer (RCC) has not been reported. We hypothesized that sFRP-5 may be epigenetically downregulated through DNA methylation and histone modification and function as a tumor suppressor gene in RCC. Using tissue microarray and real-time RT-PCR, we found that sFRP-5 was significantly downregulated in kidney cancer tissues and cell lines, respectively. DNA bisulfite sequencing of the sFRP-5 promoter region in RCC cell lines showed it to be densely methylated, whereas there was few promoter methylation in normal kidney. The sFRP-5 expression was restored and the acetylation of H3 and H4 histones associated with the sFRP-5 promoter region were significantly increased after treatment with demethylation agent (5-Aza-dc) and histone deacetylase inhibitor (TSA). When RCC cells were transfected with the sFRP-5 gene, significant inhibition of anchorage independent colony formation and cell invasion were observed compared to controls. The sFRP-5 transfection also significantly induced apoptosis in RCC cells. In conclusion, this is the first report documenting that the sFRP-5 is downregulated by promoter methylation and histone acetylation and functions as a tumor suppressor gene by inducing apoptosis in RCC cells.

Original languageEnglish (US)
Pages (from-to)541-550
Number of pages10
JournalInternational Journal of Cancer
Volume128
Issue number3
DOIs
StatePublished - Feb 1 2011

Keywords

  • RCC
  • histone modification
  • methylation
  • sFRP-5
  • tumor suppressor

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Kawakami, K., Yamamura, S., Hirata, H., Ueno, K., Saini, S., Majid, S., Tanaka, Y., Kawamoto, K., Enokida, H., Nakagawa, M., & Dahiya, R. (2011). Secreted frizzled-related protein-5 is epigenetically downregulated and functions as a tumor suppressor in kidney cancer. International Journal of Cancer, 128(3), 541-550. https://doi.org/10.1002/ijc.25357