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MYT1 attenuates neuroblastoma cell differentiation by interacting with the LSD1/CoREST complex

Oncogene volume 39, pages 4212–4226 (2020)Cite this article

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Abstract

Impaired neuronal differentiation is a feature of neuroblastoma tumorigenesis, and the differentiation grade of neuroblastoma tumors is associated with patient prognosis. Detailed understanding of the molecular mechanisms underlying neuroblastoma differentiation will facilitate the development of effective treatment strategies. Recent studies have shown that myelin transcription factor 1 (MYT1) promotes vertebrate neurogenesis by regulating gene expression. We performed quantitative analysis of neuroblastoma samples, which revealed that MYT1 was differentially expressed among neuroblastoma patients with different pathological diagnoses. Analysis of clinical data showed that MYT1 overexpression was associated with a significantly shorter 3-year overall survival rate and poor differentiation in neuroblastoma specimens. MYT1 knockdown inhibited proliferation and promoted the expression of multiple differentiation-associated proteins. Integrated omics data indicated that many genes involved in neuro-differentiation were regulated by MYT1. Interestingly, many of these genes are targets of the REST complex; therefore, we further identified the physical interaction of MYT1 with LSD1/CoREST. Depletion of LSD1 or inhibition of LSD1 by ORY-1001 decreased MYT1 expression, providing an alternative approach to target MYT1. Taken together, our results indicate that MYT1 significantly attenuates cell differentiation by interacting with the LSD1/CoREST complex. MYT1 is, therefore, a promising therapeutic target for enhancing the neurite-inducing effect of retinoic acid and for inhibiting the growth of neuroblastoma.

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Fig. 1: MYT1 is expressed in neuroblastoma tissue.
Fig. 2: Downregulation of MYT1 is associated with differentiated neuroblastoma.
Fig. 3: Downregulation of MYT1 could inhibit neuroblastoma proliferation.
Fig. 4: Bioinformatic characterization of MYT1 molecules identified by RNA sequencing and quantitative proteomics.
Fig. 5: MYT1 regulates downstream genes by incorporation of the LSD1/CoREST complex.
Fig. 6: LSD1 is expressed in neuroblastoma tissue and is related to MYT1.

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Acknowledgements

This work is supported by the Natural Science Foundation of China (No. 81572918) and Suzhou Clinical Medicine Innovation Team Introduction Project (SZYJTD201706) to YW, Shanghai Jiao Tong University School of Medicine Doctoral Innovation Fund (No. BXJ201826) to KC, Natural Science Foundation of China (No. 81402478), Shanghai Rising-Star Program (16QA1402900) to ZW, and Natural Science Foundation of China (No. 81672488) to GX. We thank Lisa Kreiner, PhD, from Liwen Bianji, Edanz Editing China (www.liwenbianji.cn/ac), for editing the English text of a draft of this paper.

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  1. These authors contributed equally: Kai Chen, Yuanxia Cai

Authors and Affiliations

  1. Department of Pediatric Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200092, China

    Kai Chen, Yuanxia Cai, Cheng Cheng, Fan Lv, Peiwen Duan, Yeming Wu & Zhixiang Wu

  2. Division of Pediatric Oncology, Shanghai Institute of Pediatric Research, Shanghai, 200092, China

    Kai Chen, Yuanxia Cai, Cheng Cheng, Fan Lv, Peiwen Duan, Yeming Wu & Zhixiang Wu

  3. Department of Pediatric Urology, Xinhua Hospital, National Key Clinical Specialty, Shanghai Top-Priority Clinical Center, School of Medicine, Shanghai Jiaotong University, Shanghai, 200092, China

    Junqi Zhang & Guofeng Xu

  4. Department of Pediatric Surgery, Children’s Hospital of Soochow University, Suzhou, 215003, China

    Fan Lv, Yeming Wu & Zhixiang Wu

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Chen, K., Cai, Y., Cheng, C. et al. MYT1 attenuates neuroblastoma cell differentiation by interacting with the LSD1/CoREST complex. Oncogene 39, 4212–4226 (2020). https://doi.org/10.1038/s41388-020-1268-6

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