2. Academic Validation
  3. NeuroD1 Dictates Tumor Cell Differentiation in Medulloblastoma

NeuroD1 Dictates Tumor Cell Differentiation in Medulloblastoma

  • Cell Rep. 2020 Jun 23;31(12):107782. doi: 10.1016/j.celrep.2020.107782.
Yan Cheng 1,  Shengyou Liao 2,  Gang Xu 3,  Jian Hu 1,  Duancheng Guo 4,  Fang Du 3,  Alejandra Contreras 5,  Kathy Q Cai 3,  Suraj Peri 6,  Yuan Wang 4,  David C Corney 7,  Anne Marie Noronha 7,  Lianne Q Chau 8,  Ginger Zhou 7,  David L Wiest 5,  Alfonso Bellacosa 3,  Robert J Wechsler-Reya 8,  Yi Zhao 2,  Zeng-Jie Yang 9
Affiliations

Affiliations

  • 1 Cancer Biology Program, Fox Chase Cancer Center, Temple University Health System, Philadelphia, PA, USA; Laboratory of Molecular Neuropathology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
  • 2 Bioinformatics Research Group, Chinese Academy of Sciences, Beijing, China.
  • 3 Cancer Biology Program, Fox Chase Cancer Center, Temple University Health System, Philadelphia, PA, USA.
  • 4 Laboratory of Molecular Neuropathology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
  • 5 Blood Cell Development and Function, Fox Chase Cancer Center, Temple University Health System, Philadelphia, PA, USA.
  • 6 Biostatistics and Bioinformatics Research Facility, Fox Chase Cancer Center, Temple University Health System, Philadelphia, PA, USA.
  • 7 Genomics and Molecular Genetics, GENEWIZ Co., South Plainfield, NJ, USA.
  • 8 Tumor Initiation& Maintenance Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
  • 9 Cancer Biology Program, Fox Chase Cancer Center, Temple University Health System, Philadelphia, PA, USA. Electronic address: zengjie.yang@fccc.edu.
PMID: 32579914 DOI: 10.1016/j.celrep.2020.107782
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

EZH2 inhibitors; H3k27me3; NeuroD1; Tag1; differentiation therapy; epigenetic compound screening; granule neuron precursors; hedgehog signaling; medulloblastoma; tumor cell differentiation.

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