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13-Cis Retinoic Acid Induces Neuronal Differentiation in Daoy (Medulloblastoma) Cells Through Epigenetic Regulation of Topoisomerase IIβ

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Abstract

Medulloblastoma (MB) is a malignant tumor of the cerebellum that occurs in children and infants. Abnormal neuronal differentiation can lead to brain tumors, and topoisomerase IIβ (Top IIβ) plays an important role in neuronal differentiation. The aim of this study was to investigate the molecular mechanism of 13-cis retinoic acid (13-cis RA) promoting the expression of Top IIβ and inducing neuronal differentiation in human MB Daoy cells. The results showed that 13-cis RA inhibited the cell proliferation and induced cell cycle arrest in G0/G1 phase. The cells differentiated into a neuronal phenotype, with high expression of the neuronal marker microtubule-associated protein 2 (MAP2) and abundant Top IIβ, and obvious neurite growth. Chromatin immunoprecipitation (ChIP) assay showed that histone H3 lysine 27 tri-methylation (H3K27me3) modification in Top IIβ promoter decreased after 13-cis RA-induced cell differentiation, while jumonji domain-containing protein 3 (JMJD3) binding in Top IIβ promoter increased. These results suggest that H3K27me3 and JMJD3 can regulate the expression of Top IIβ gene, which is related to inducing neural differentiation. Our results provide new insights into understanding the regulatory mechanisms of Top IIβ during neuronal differentiation and imply the potential application of 13-cis RA in the clinical treatment of MB.

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Data Availability

All data generated or analysed during this study are included in this published article and its supplementary information files.

Abbreviations

13-cis RA:

13-Cis retinoic acid

Top IIβ:

Topoisomerase IIβ

MAP2:

Microtubule-associated protein 2

ChIP:

Chromatin immunoprecipitation

H3K27me3:

Histone H3 lysine 27 tri-methylation

JMJD3:

Jumonji domain-containing protein 3

MB:

Medulloblastoma

CNS:

Central nervous system

DMB:

Desmoplastic medulloblastoma

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Funding

The work was supported by the University Science and Technology Research Project of Hebei Province (QN2017107).

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Authors and Affiliations

  1. Department of Cell Biology, College of Basic Medicine, Hebei Medical University, Shijiazhuang, 050017, Hebei, People’s Republic of China

    Jing Chen, Xing-Yu Li, Yong-Xin Yan, Yan-Ling Wang, Yu-Hong Lv, Yun-Li Yan & Yu-Hua Lei

  2. Department of Radiology, Shijiazhuang Second Hospital, Shijiazhuang, Hebei, China

    Jing-Xia Zhang

  3. Department of Oncology, Hebei General Hospital, Shijiazhuang, Hebei, China

    Hai-Xia Lei

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Contributions

Jing Chen: conceptualization, methodology, writing—original draft, formal analysis. Jing-Xia Zhang: methodology, formal analysis, validation. Hai-Xia Lei: methodology, validation. Xing-Yu Li: data curation, formal analysis. Yong-Xin Yan: formal analysis, validation. Yan-Ling Wang: methodology, data curation. Yu-Hong Lv: funding acquisition, resources. Yun-Li Yan: project administration. Yu-Hua Lei: writing—reviewing and editing, supervision, project administration.

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Chen, J., Zhang, JX., Lei, HX. et al. 13-Cis Retinoic Acid Induces Neuronal Differentiation in Daoy (Medulloblastoma) Cells Through Epigenetic Regulation of Topoisomerase IIβ. Appl Biochem Biotechnol 195, 7429–7445 (2023). https://doi.org/10.1007/s12010-023-04476-z

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