Characterization and pharmacologic targeting of EZH2, a fetal retinal protein and epigenetic regulator, in human retinoblastoma

Mehnaz Khan; Laura L Walters; Qiang Li; Dafydd G Thomas; Jason M L Miller; Qitao Zhang; Andrew P Sciallis; Yu Liu; Brian J Dlouhy; Patrice E Fort; Steven M Archer; Hakan Demirci; Yali Dou; Rajesh C Rao

doi:10.1038/labinvest.2015.104

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Characterization and pharmacologic targeting of EZH2, a fetal retinal protein and epigenetic regulator, in human retinoblastoma

Journal article

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Characterization and pharmacologic targeting of EZH2, a fetal retinal protein and epigenetic regulator, in human retinoblastoma

Mehnaz Khan, Laura L Walters, Qiang Li, Dafydd G Thomas, Jason M L Miller, Qitao Zhang, Andrew P Sciallis, Yu Liu, Brian J Dlouhy, Patrice E Fort, …

Laboratory investigation, Vol.95(11), pp.1278-1290

11/2015

DOI: 10.1038/labinvest.2015.104

PMCID: PMC4626270

PMID: 26280220

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Abstract

Retinoblastoma (RB) is the most common primary intraocular cancer in children, and the third most common cancer overall in infants. No molecular-targeted therapy for this lethal tumor exists. Since the tumor suppressor RB1, whose genetic inactivation underlies RB, is upstream of the epigenetic regulator EZH2, a pharmacologic target for many solid tumors, we reasoned that EZH2 might regulate human RB tumorigenesis. Histologic and immunohistochemical analyses were performed using an EZH2 antibody in sections from 43 samples of primary, formalin-fixed, paraffin-embedded human RB tissue, cryopreserved mouse retina, and in whole cell lysates from human RB cell lines (Y79 and WERI-Rb1), primary human fetal retinal pigment epithelium (RPE) and fetal and adult retina, mouse retina and embryonic stem (ES) cells. Although enriched during fetal human retinal development, EZH2 protein was not present in the normal postnatal retina. However, EZH2 was detected in all 43 analyzed human RB specimens, indicating that EZH2 is a fetal protein expressed in postnatal human RB. EZH2 expression marked single RB cell invasion into the optic nerve, a site of invasion whose involvement may influence the decision for systemic chemotherapy. To assess the role of EZH2 in RB cell survival, human RB and primary RPE cells were treated with two EZH2 inhibitors (EZH2i), GSK126 and SAH-EZH2 (SAH). EZH2i impaired intracellular adenosine triphosphate (ATP) production, an indicator of cell viability, in a time and dose-dependent manner, but did not affect primary human fetal RPE. Thus, aberrant expression of a histone methyltransferase protein is a feature of human RB. This is the first time this mechanism has been implicated for an eye, adnexal, or orbital tumor. The specificity of EZH2i toward human RB cells, but not RPE, warrants further in vivo testing in animal models of RB, especially those EZH2i currently in clinical trials for solid tumors and lymphoma.

Humans

Retinal Neoplasms - pathology

Child, Preschool

Polycomb Repressive Complex 2 - drug effects

Infant

Male

Retinoblastoma - metabolism

Retinoblastoma - pathology

Enhancer of Zeste Homolog 2 Protein

Epigenesis, Genetic - physiology

Animals

Polycomb Repressive Complex 2 - physiology

Cell Line, Tumor

Female

Mice

Retinal Neoplasms - metabolism

Polycomb Repressive Complex 2 - metabolism

Details

Title: Subtitle: Characterization and pharmacologic targeting of EZH2, a fetal retinal protein and epigenetic regulator, in human retinoblastoma
Creators: Mehnaz Khan - Department of Ophthalmology and Visual Sciences, W.K. Kellogg Eye Center, University of Michigan Medical School, Ann Arbor, MI, USA
Laura L Walters - Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA
Qiang Li - Department of Ophthalmology and Visual Sciences, W.K. Kellogg Eye Center, University of Michigan Medical School, Ann Arbor, MI, USA
Dafydd G Thomas - Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA
Jason M L Miller - Department of Ophthalmology and Visual Sciences, W.K. Kellogg Eye Center, University of Michigan Medical School, Ann Arbor, MI, USA
Qitao Zhang - Department of Ophthalmology and Visual Sciences, W.K. Kellogg Eye Center, University of Michigan Medical School, Ann Arbor, MI, USA
Andrew P Sciallis - Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA
Yu Liu - Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
Brian J Dlouhy - Department of Neurosurgery, University of Iowa Hospitals & Clinics, Iowa City, IA, USA
Patrice E Fort - Department of Ophthalmology and Visual Sciences, W.K. Kellogg Eye Center, University of Michigan Medical School, Ann Arbor, MI, USA
Steven M Archer - Department of Ophthalmology and Visual Sciences, W.K. Kellogg Eye Center, University of Michigan Medical School, Ann Arbor, MI, USA
Hakan Demirci - Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA
Yali Dou - Department of Biochemistry, University of Michigan Medical School, Ann Arbor, MI, USA
Rajesh C Rao - Section of Ophthalmology, Surgical Service, Veterans Administration Ann Arbor Healthcare System, Ann Arbor, MI, USA
Resource Type: Journal article
Publication Details: Laboratory investigation, Vol.95(11), pp.1278-1290
Publisher: United States
DOI: 10.1038/labinvest.2015.104
PMID: 26280220
PMCID: PMC4626270
ISSN: 0023-6837
eISSN: 1530-0307
Grant note: R01 EY020895 / NEI NIH HHS K12 EY022299 / NEI NIH HHS T32 EY013934 / NEI NIH HHS K12EY022299 / NEI NIH HHS T32EY013934 / NEI NIH HHS
Language: English
Date published: 11/2015
Academic Unit: Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Neurosurgery
Record Identifier: 9984040345402771

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