NeuroD1 Dictates Tumor Cell Differentiation in Medulloblastoma

Yan Cheng; Shengyou Liao; Gang Xu; Duancheng Guo; Fang Du; Alejandra V. Contreras; Kathy Cai; Suraj Peri; Yuan Wang; David C. Corney; Anne Marie Noronha; Lianne Q. Chau; Ginger Zhou; David Wiest; Alfonso Bellacosa; Robert J. Wechsler-Reya; Yi Zhao; Zeng Jie Yang

doi:10.1016/j.celrep.2020.107782

NeuroD1 Dictates Tumor Cell Differentiation in Medulloblastoma

Yan Cheng
, Shengyou Liao
, Gang Xu
, Duancheng Guo
, Fang Du
, Alejandra V. Contreras
, Kathy Cai
, Suraj Peri
, Yuan Wang
, David C. Corney
, Anne Marie Noronha
, Lianne Q. Chau
, Ginger Zhou
, David Wiest
, Alfonso Bellacosa
, Robert J. Wechsler-Reya
, Yi Zhao
, Zeng Jie Yang

Temple University
Soochow University
University of Chinese Academy of Sciences
GENEWIZ, Inc.
Sanford Burnham Prebys Medical Discovery Institute
CAS - Institute of Computing Technology
Central South University
University of South China
Fox Chase Cancer Center
Department of Biostatistics and Bioinformatics
Department of Biostatistics
Merck & Co.
University of Pennsylvania
Duke University

Research output: Contribution to journal › Article › peer-review

52 Scopus citations

Abstract

Tumor cells are characterized by unlimited proliferation and perturbed differentiation. Using single-cell RNA sequencing, we demonstrate that tumor cells in medulloblastoma (MB) retain their capacity to differentiate in a similar way as their normal originating cells, cerebellar granule neuron precursors. Once they differentiate, MB cells permanently lose their proliferative capacity and tumorigenic potential. Differentiated MB cells highly express NeuroD1, a helix-loop-helix transcription factor, and forced expression of NeuroD1 promotes the differentiation of MB cells. The expression of NeuroD1 in bulk MB cells is repressed by trimethylation of histone 3 lysine-27 (H3K27me3). Inhibition of the histone lysine methyltransferase EZH2 prevents H3K27 trimethylation, resulting in increased NeuroD1 expression and enhanced differentiation in MB cells, which consequently reduces tumor growth. These studies reveal the mechanisms underlying MB cell differentiation and provide rationales to treat MB (potentially other malignancies) by stimulating tumor cell differentiation.

Original language	English
Article number	107782
Pages (from-to)	107782
Journal	Cell Reports
Volume	31
Issue number	12
DOIs	https://doi.org/10.1016/j.celrep.2020.107782
State	Published - Jun 23 2020

Keywords

Animals
Basic Helix-Loop-Helix Transcription Factors/metabolism
Carcinogenesis/pathology
Cell Differentiation
Cell Line, Tumor
Cell Proliferation
Cerebellar Neoplasms/pathology
Enhancer of Zeste Homolog 2 Protein/metabolism
Hedgehog Proteins/metabolism
Histones/metabolism
Humans
Lysine/metabolism
Medulloblastoma/pathology
Methylation
Mice
Nerve Tissue Proteins/metabolism
Neurons/metabolism
Patched-1 Receptor/metabolism
Signal Transduction
Single-Cell Analysis

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10.1016/j.celrep.2020.107782

Cite this

Cheng, Y., Liao, S., Xu, G., Guo, D., Du, F., Contreras, A. V., Cai, K., Peri, S., Wang, Y., Corney, D. C., Noronha, A. M., Chau, L. Q., Zhou, G., Wiest, D., Bellacosa, A., Wechsler-Reya, R. J., Zhao, Y., & Yang, Z. J. (2020). NeuroD1 Dictates Tumor Cell Differentiation in Medulloblastoma. Cell Reports, 31(12), 107782. Article 107782. https://doi.org/10.1016/j.celrep.2020.107782

@article{2273246a30314bc29afebf610452664d,

title = "NeuroD1 Dictates Tumor Cell Differentiation in Medulloblastoma",

abstract = "Tumor cells are characterized by unlimited proliferation and perturbed differentiation. Using single-cell RNA sequencing, we demonstrate that tumor cells in medulloblastoma (MB) retain their capacity to differentiate in a similar way as their normal originating cells, cerebellar granule neuron precursors. Once they differentiate, MB cells permanently lose their proliferative capacity and tumorigenic potential. Differentiated MB cells highly express NeuroD1, a helix-loop-helix transcription factor, and forced expression of NeuroD1 promotes the differentiation of MB cells. The expression of NeuroD1 in bulk MB cells is repressed by trimethylation of histone 3 lysine-27 (H3K27me3). Inhibition of the histone lysine methyltransferase EZH2 prevents H3K27 trimethylation, resulting in increased NeuroD1 expression and enhanced differentiation in MB cells, which consequently reduces tumor growth. These studies reveal the mechanisms underlying MB cell differentiation and provide rationales to treat MB (potentially other malignancies) by stimulating tumor cell differentiation.",

keywords = "Animals, Basic Helix-Loop-Helix Transcription Factors/metabolism, Carcinogenesis/pathology, Cell Differentiation, Cell Line, Tumor, Cell Proliferation, Cerebellar Neoplasms/pathology, Enhancer of Zeste Homolog 2 Protein/metabolism, Hedgehog Proteins/metabolism, Histones/metabolism, Humans, Lysine/metabolism, Medulloblastoma/pathology, Methylation, Mice, Nerve Tissue Proteins/metabolism, Neurons/metabolism, Patched-1 Receptor/metabolism, Signal Transduction, Single-Cell Analysis",

author = "Yan Cheng and Shengyou Liao and Gang Xu and Duancheng Guo and Fang Du and Contreras, \{Alejandra V.\} and Kathy Cai and Suraj Peri and Yuan Wang and Corney, \{David C.\} and Noronha, \{Anne Marie\} and Chau, \{Lianne Q.\} and Ginger Zhou and David Wiest and Alfonso Bellacosa and Wechsler-Reya, \{Robert J.\} and Yi Zhao and Yang, \{Zeng Jie\}",

year = "2020",

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doi = "10.1016/j.celrep.2020.107782",

language = "English",

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T1 - NeuroD1 Dictates Tumor Cell Differentiation in Medulloblastoma

AU - Cheng, Yan

AU - Liao, Shengyou

AU - Xu, Gang

AU - Guo, Duancheng

AU - Du, Fang

AU - Contreras, Alejandra V.

AU - Cai, Kathy

AU - Peri, Suraj

AU - Wang, Yuan

AU - Corney, David C.

AU - Noronha, Anne Marie

AU - Chau, Lianne Q.

AU - Zhou, Ginger

AU - Wiest, David

AU - Bellacosa, Alfonso

AU - Wechsler-Reya, Robert J.

AU - Zhao, Yi

AU - Yang, Zeng Jie

PY - 2020/6/23

Y1 - 2020/6/23

N2 - Tumor cells are characterized by unlimited proliferation and perturbed differentiation. Using single-cell RNA sequencing, we demonstrate that tumor cells in medulloblastoma (MB) retain their capacity to differentiate in a similar way as their normal originating cells, cerebellar granule neuron precursors. Once they differentiate, MB cells permanently lose their proliferative capacity and tumorigenic potential. Differentiated MB cells highly express NeuroD1, a helix-loop-helix transcription factor, and forced expression of NeuroD1 promotes the differentiation of MB cells. The expression of NeuroD1 in bulk MB cells is repressed by trimethylation of histone 3 lysine-27 (H3K27me3). Inhibition of the histone lysine methyltransferase EZH2 prevents H3K27 trimethylation, resulting in increased NeuroD1 expression and enhanced differentiation in MB cells, which consequently reduces tumor growth. These studies reveal the mechanisms underlying MB cell differentiation and provide rationales to treat MB (potentially other malignancies) by stimulating tumor cell differentiation.

AB - Tumor cells are characterized by unlimited proliferation and perturbed differentiation. Using single-cell RNA sequencing, we demonstrate that tumor cells in medulloblastoma (MB) retain their capacity to differentiate in a similar way as their normal originating cells, cerebellar granule neuron precursors. Once they differentiate, MB cells permanently lose their proliferative capacity and tumorigenic potential. Differentiated MB cells highly express NeuroD1, a helix-loop-helix transcription factor, and forced expression of NeuroD1 promotes the differentiation of MB cells. The expression of NeuroD1 in bulk MB cells is repressed by trimethylation of histone 3 lysine-27 (H3K27me3). Inhibition of the histone lysine methyltransferase EZH2 prevents H3K27 trimethylation, resulting in increased NeuroD1 expression and enhanced differentiation in MB cells, which consequently reduces tumor growth. These studies reveal the mechanisms underlying MB cell differentiation and provide rationales to treat MB (potentially other malignancies) by stimulating tumor cell differentiation.

KW - Animals

KW - Basic Helix-Loop-Helix Transcription Factors/metabolism

KW - Carcinogenesis/pathology

KW - Cell Differentiation

KW - Cell Line, Tumor

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KW - Cerebellar Neoplasms/pathology

KW - Enhancer of Zeste Homolog 2 Protein/metabolism

KW - Hedgehog Proteins/metabolism

KW - Histones/metabolism

KW - Humans

KW - Lysine/metabolism

KW - Medulloblastoma/pathology

KW - Methylation

KW - Mice

KW - Nerve Tissue Proteins/metabolism

KW - Neurons/metabolism

KW - Patched-1 Receptor/metabolism

KW - Signal Transduction

KW - Single-Cell Analysis

UR - https://www.scopus.com/pages/publications/85087093506

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DO - 10.1016/j.celrep.2020.107782

M3 - Article

C2 - 32579914

SN - 2211-1247

VL - 31

SP - 107782

JO - Cell Reports

JF - Cell Reports

IS - 12

M1 - 107782

ER -

NeuroD1 Dictates Tumor Cell Differentiation in Medulloblastoma

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NeuroD1 Dictates Tumor Cell Differentiation in Medulloblastoma

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