Inhibition of EZH2 suppresses self-renewal and induces radiation sensitivity in atypical rhabdoid teratoid tumor cells. Neuro Oncol 2013 Feb;15(2):149-60
Date
11/30/2012Pubmed ID
23190500Pubmed Central ID
PMC3548579DOI
10.1093/neuonc/nos285Scopus ID
2-s2.0-84875715709 (requires institutional sign-in at Scopus site) 120 CitationsAbstract
INTRODUCTION: Overexpression of the Polycomb repressive complex 2 (PRC2) subunit Enhancer of Zeste 2 (EZH2) occurs in several malignancies, including prostate cancer, breast cancer, medulloblastoma, and glioblastoma multiforme. Recent evidence suggests that EZH2 may also have a role in rhabdoid tumors. Atypical teratoid/rhabdoid tumor (ATRT) is a rare, high-grade embryonal brain tumor that occurs most commonly in young children and carries a very poor prognosis. ATRTs are characterized by absence of the chromatin remodeling protein SMARCB1. Given the role of EZH2 in regulating epigenetic changes, we investigated the role of EZH2 in ATRT.
METHODS: Microarray analysis was used to evaluate expression of EZH2 in ATRT tumor samples. We used shRNA and a chemical inhibitor of EZH2 to examine the impact of EZH2 inhibition on cell growth, proliferation, and tumor cell self-renewal.
RESULTS: Here, we show that targeted disruption of EZH2 by RNAi or pharmacologic inhibition strongly impairs ATRT cell growth, suppresses tumor cell self-renewal, induces apoptosis, and potently sensitizes these cells to radiation. Using functional analysis of transcription factor activity, we found the cyclin D1-E2F axis to be repressed after EZH2 depletion in ATRT cells.
CONCLUSIONS: Our observations provide evidence that EZH2 disruption alters cell cycle progression and may be an important new therapeutic target, particularly in combination with radiation, in ATRT.
Author List
Alimova I, Birks DK, Harris PS, Knipstein JA, Venkataraman S, Marquez VE, Foreman NK, Vibhakar RMESH terms used to index this publication - Major topics in bold
AdolescentApoptosis
Biomarkers, Tumor
Blotting, Western
Cell Cycle
Cell Proliferation
Cellular Senescence
Cerebellum
Child
Enhancer of Zeste Homolog 2 Protein
Gene Expression Profiling
Humans
Immunoenzyme Techniques
Oligonucleotide Array Sequence Analysis
Polycomb Repressive Complex 2
RNA, Messenger
RNA, Small Interfering
Radiation Tolerance
Real-Time Polymerase Chain Reaction
Reverse Transcriptase Polymerase Chain Reaction
Rhabdoid Tumor
Spheroids, Cellular
Teratoma
Tumor Cells, Cultured
