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J Clin Invest. 2018 Jan 2;128(1):446-462. doi: 10.1172/JCI90793. Epub 2017 Dec 4.

CRISPR-Cas9 screen reveals a MYCN-amplified neuroblastoma dependency on EZH2.

Author information

1
Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, Massachusetts, USA.
2
Broad Institute, Cambridge, Massachusetts, USA.
3
Harvard Medical School, Boston, Massachusetts, USA.
4
Bioinformatics Graduate Program, Boston University, Boston, Massachusetts, USA.
5
Cell and Molecular Biology Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA.
6
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
7
Department of Pediatrics, Helen Diller Family Comprehensive Cancer Center, UCSF, San Francisco, California, USA.
8
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
9
Comprehensive Cancer Center and Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
10
Department of Neurology, Neurological Surgery, Brain Tumor Research Center, UCSF, San Francisco, California, USA.

Abstract

Pharmacologically difficult targets, such as MYC transcription factors, represent a major challenge in cancer therapy. For the childhood cancer neuroblastoma, amplification of the oncogene MYCN is associated with high-risk disease and poor prognosis. Here, we deployed genome-scale CRISPR-Cas9 screening of MYCN-amplified neuroblastoma and found a preferential dependency on genes encoding the polycomb repressive complex 2 (PRC2) components EZH2, EED, and SUZ12. Genetic and pharmacological suppression of EZH2 inhibited neuroblastoma growth in vitro and in vivo. Moreover, compared with neuroblastomas without MYCN amplification, MYCN-amplified neuroblastomas expressed higher levels of EZH2. ChIP analysis showed that MYCN binds at the EZH2 promoter, thereby directly driving expression. Transcriptomic and epigenetic analysis, as well as genetic rescue experiments, revealed that EZH2 represses neuronal differentiation in neuroblastoma in a PRC2-dependent manner. Moreover, MYCN-amplified and high-risk primary tumors from patients with neuroblastoma exhibited strong repression of EZH2-regulated genes. Additionally, overexpression of IGFBP3, a direct EZH2 target, suppressed neuroblastoma growth in vitro and in vivo. We further observed strong synergy between histone deacetylase inhibitors and EZH2 inhibitors. Together, these observations demonstrate that MYCN upregulates EZH2, leading to inactivation of a tumor suppressor program in neuroblastoma, and support testing EZH2 inhibitors in patients with MYCN-amplified neuroblastoma.

KEYWORDS:

Epigenetics; Oncology

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