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Epigenetic inactivation of MCJ (DNAJD1) in malignant paediatric brain tumours

Lookup NU author(s): Dr Janet Lindsey, Dr Meryl Lusher, Dr Gordon Strathdee, Dr Richard Gilbertson, Professor Simon Bailey, Professor David Ellison, Professor Steven Clifford

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Abstract

MCJ (DNAJD1) is a recently discovered member of the DNAJ protein family whose expression is controlled epigenetically by methylation of a CpG island located within the 5' transcribed region of its gene. Methylation-dependent transcriptional silencing of MCJ has been observed in ovarian cancers and associated with increased resistance to chemotherapeutic agents; however, its role in other cancer types has not been widely investigated. We examined the status of MCJ in intracranial primitive neuroectodermal tumours [PNETs, comprising cerebellar PNETs (medulloblastomas) and supratentorial PNETs (stPNETs)] and ependymomas, together representing the most common malignant brain tumours of childhood. Evidence of MCJ hypermethylation was found in all 3 tumour types [medulloblastomas, 3/9 (33%) cell lines, 2/28 (7%) primary tumours; stPNETs, 2/2 (100%) cell lines, 3/10 (30%) primary tumours; and ependymomas, 2/20 (10%) primary tumours] but not in nonneoplastic brain tissues (n = 11), indicating that MCJ methylation is a tumour-specific event. In methylated cases, the distribution of methylated CpG sites across the CpG island could be broadly divided into 2 patterns: (i) extensive methylation of the majority of CpG sites across the island or (ii) limited methylation of individual CpG sites concentrated towards the 5' end of the island. Extensive methylation patterns were associated with the methylation-dependent transcriptional silencing of MCJ in medulloblastoma and stPNET cell lines. Further investigations of the mechanism of MCJ inactivation revealed that its loss could occur either through biallelic epigenetic methylation or by methylation in association with genetic loss of its second allele. These data indicate that epigenetic inactivation of MCJ may play a role in the development of a range of paediatric brain tumour types, and its role in disease pathogenesis and chemotherapeutic resistance should now be investigated further.


Publication metadata

Author(s): Lindsey JC, Lusher ME, Strathdee G, Brown R, Gilbertson RJ, Bailey S, Ellison DW, Clifford SC

Publication type: Article

Publication status: Published

Journal: International Journal of Cancer

Year: 2006

Volume: 118

Issue: 2

Pages: 346-352

ISSN (print): 0020-7136

ISSN (electronic): 1097-0215

Publisher: John Wiley & Sons, Inc.

URL: http://dx.doi.org/10.1002/ijc.21353

DOI: 10.1002/ijc.21353

Notes: Lindsey, Janet C Lusher, Meryl E Strathdee, Gordon Brown, Robert Gilbertson, Richard J Bailey, Simon Ellison, David W Clifford, Steven C Research Support, Non-U.S. Gov't United States International journal of cancer. Journal international du cancer Int J Cancer. 2006 Jan 15;118(2):346-52.


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