Epigenetic inactivation of the RASSF10 candidate tumor suppressor gene is a frequent and an early event in gliomagenesis

V K Hill, N Underhill-Day, D Krex, K Robel, C B Sangan, H R Summersgill, M Morris, D Gentle, Andrew D Chalmers, E R Maher, F Latif

Research output: Contribution to journalArticle

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Abstract

We have recently described the N-terminal RAS association domain family of genes, RASSF7-10. Previously, we cloned the N-terminal RASSF10 gene and demonstrated frequent methylation of the associated 50-CpG island in acute lymphoblastic leukemia. To characterize RASSF10 gene expression, we demonstrate that in developing Xenopus embryos, RASSF10 shows a very striking pattern in the rhombencephalon (hind brain). It is also expressed in other parts of the brain and other organs. Due to the well-defined expression pattern in the brain of Xenopus embryos, we analyzed the methylation status of the RASSF10-associated 5'-CpG island in astrocytic gliomas. RASSF10 was frequently methylated in WHO grade II-III astrocytomas and WHO grade IV primary glioblastomas (67.5%), but was unmethylated in grade I astrocytomas and in DNA from age matched control brain samples. RASSF10 gene expression both at the mRNA and protein levels could be switched back on in methylated glioma cell lines after treatment with 5-aza-2'-deoxycytidine. In secondary glioblastomas (sGBM), RASSF10 methylation was an independent prognostic factor associated with worst progression-free survival and overall survival and occurred at an early stage in their development. In cell culture experiments, overexpression of RASSF10 mediated a reduction in the colony forming ability of two RASSF10-methylated glioma cell lines. Conversely, RNAi-mediated knockdown of RASSF10-stimulated anchorage-independent growth of U87 glioma cells, increased their viability and caused an increase in the cells' proliferative ability. We generated and characterized a RASSF10-specific antibody and demonstrated for the first time that RASSF10 subcellular localization is cell-cycle dependent with RASSF10 colocalizing to centrosomes and associated microtubules during mitosis. This is the first report demonstrating that RASSF10 can act as a tumor suppressor gene and is frequently methylated in gliomas and can potentially be developed into a prognostic marker for sGBM.
Original languageEnglish
Pages (from-to)978-989
Number of pages12
JournalOncogene
Volume30
Issue number8
DOIs
Publication statusPublished - Feb 2011

Fingerprint

Astrocytoma
Tumor Suppressor Genes
Epigenomics
Glioma
Glioblastoma
Methylation
Rhombencephalon
CpG Islands
decitabine
Xenopus
Brain
Embryonic Structures
Gene Expression
Cell Line
Centrosome
RNA Interference
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Mitosis
Microtubules
Genes

Keywords

  • epigenetics
  • RASSF10
  • gliomas

Cite this

Hill, V. K., Underhill-Day, N., Krex, D., Robel, K., Sangan, C. B., Summersgill, H. R., ... Latif, F. (2011). Epigenetic inactivation of the RASSF10 candidate tumor suppressor gene is a frequent and an early event in gliomagenesis. Oncogene, 30(8), 978-989. https://doi.org/10.1038/onc.2010.471

Epigenetic inactivation of the RASSF10 candidate tumor suppressor gene is a frequent and an early event in gliomagenesis. / Hill, V K; Underhill-Day, N; Krex, D; Robel, K; Sangan, C B; Summersgill, H R; Morris, M; Gentle, D; Chalmers, Andrew D; Maher, E R; Latif, F.

In: Oncogene, Vol. 30, No. 8, 02.2011, p. 978-989.

Research output: Contribution to journalArticle

Hill, VK, Underhill-Day, N, Krex, D, Robel, K, Sangan, CB, Summersgill, HR, Morris, M, Gentle, D, Chalmers, AD, Maher, ER & Latif, F 2011, 'Epigenetic inactivation of the RASSF10 candidate tumor suppressor gene is a frequent and an early event in gliomagenesis', Oncogene, vol. 30, no. 8, pp. 978-989. https://doi.org/10.1038/onc.2010.471
Hill, V K ; Underhill-Day, N ; Krex, D ; Robel, K ; Sangan, C B ; Summersgill, H R ; Morris, M ; Gentle, D ; Chalmers, Andrew D ; Maher, E R ; Latif, F. / Epigenetic inactivation of the RASSF10 candidate tumor suppressor gene is a frequent and an early event in gliomagenesis. In: Oncogene. 2011 ; Vol. 30, No. 8. pp. 978-989.
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