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MECP2 is a frequently amplified oncogene with a novel epigenetic mechanism that mimics the role of activated RAS in malignancy

Abstract

An unbiased genome-scale screen for unmutated genes that drive cancer growth when overexpressed identified MECP2 as a novel oncogene. MECP2 resides in a region of the X-chromosome that is significantly amplified across 18% of cancers, and many cancer cell lines have amplified, overexpressed MECP2 and are dependent on MECP2 expression for growth. MECP2 copy number gain and RAS family member alterations are mutually exclusive in several cancer types. The MECP2 splicing isoforms activate the major growth factor pathways targeted by activated RAS, the MAPK and PI3K pathways. MECP2 rescued the growth of a KRASG12C-addicted cell line after KRAS down-regulation, and activated KRAS rescues the growth of an MECP2-addicted cell line after MECP2 downregulation. MECP2 binding to the epigenetic modification 5-hydroxymethylcytosine is required for efficient transformation. These observations suggest that MECP2 is a commonly amplified oncogene with an unusual epigenetic mode of action.

Type Journal
ISBN 2159-8290 (Electronic) 2159-8274 (Linking)
Authors Neupane, M.; Clark, A. P.; Landini, S.; Birkbak, N. J.; Eklund, A. C.; Lim, E.; Culhane, A. C.; Barry, W. T.; Schumacher, S. E.; Beroukhim, R.; Szallasi, Z.; Vidal, M.; Hill, D. E.; Silver, D. P.;
Publisher Name Cancer Discovery
Published Date 2016-01-01 00:00:00
Published Volume 6
Published Issue 1
Published Pages 45-58
Status Published in-print
DOI 10.1158/2159-8290.CD-15-0341
URL link to publisher's version http://www.ncbi.nlm.nih.gov/pubmed/26546296
OpenAccess link to author's accepted manuscript version https://publications.gimr.garvan.org.au/open-access/13119