Abstract
SMARCE1 gene, encoding a core subunit of SWI/SNF chromatin remodeling complex, is situated on chromosome 17q21-ter region that is frequently gained in neuroblastoma. However, its role in the tumorigenesis remains unknown. Here, we showed that high expression of SMARCE1 was associated with poor prognosis of patients with neuroblastoma, especially those with MYCN amplification. Knockdown of SMARCE1 reduced proliferation, colony formation, and tumorigenicity of neuroblastoma cells. Mechanistically, SMARCE1 directly interacted with MYCN, which was necessary for MYCN-mediated transcriptional activation of downstream target genes including PLK1, ODC1, and E2F2. Overexpression of PLK1, ODC1 or E2F2 significantly reversed the inhibiting effect of SMARCE1 knockdown on the proliferation, colony formation, and tumorigenicity of MYCN-amplified neuroblastoma cells. Moreover, we revealed that MYCN directly regulated SMARCE1 transcription through binding to a non-canonical E-box of SMARCE1 promoter, thus enhancing SMARCE1-MYCN cooperativity. These findings establish SMARCE1 is a critical oncogenic factor in neuroblastoma and provide a new potential target for treatment of neuroblastoma with 17q21-ter gain and MYCN amplification.
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Data availability
All of the data and material in this paper are available when requested. We obtained several other publicly available ChIP-seq datasets (GSM2113542, GSM2214113, GSM2113529, GSM2113526 and ENCSR157TCS) for analysis. We also obtained 88 human Neuroblastoma samples dataset (GSE16476) for analysis (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi; https://www.encodeproject.org/).
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Acknowledgements
This research was supported by the Natural Science Foundation of Chongqing (cstc2019jcyj-zdxmX0033, cstc2022ycjh-bgzxm0145), the pilot program of Southwest University (SWU-XDZD22006).
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HC, PL and XH conceived and designed the experiments. XH, JH, WP, SW, YL, GZ and XZ performed the experiments, collected the data. XH, RL and MX analyzed the data and prepared the figures. XH and HC wrote the manuscript. All the authors read and approved the final manuscript.
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All experiments involving cancer patients’ samples were obtained from Chaoying Biotechnology Co., Ltd. (Henan, China), and the studies were approved by the Medical Ethics Committee of Tongxu County People’s Hospital of Henan Province. All of the patients were informed consent.
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Supplementary Figure 2. SMARCE1 is required for the colony-formation ability and proper cell cycle progression of MYCN-amplified neuroblastoma cells
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Supplementary Figure 6. SMARCE1 cooperate with MYCN to transcriptionally regulates the expression of PLK1, ODC1 and E2F2
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Supplementary Figure 7. The MYCN-SMARCE1 interaction is an important factor that regulates PLK1 expression and cell proliferation.
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Supplementary Figure 8. Analysis of the correlation between MYCN and SMARCE1 expression levels in several MYCN-amplified or overexpressed cancers
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Hu, X., Liu, R., Hou, J. et al. SMARCE1 promotes neuroblastoma tumorigenesis through assisting MYCN-mediated transcriptional activation. Oncogene 41, 4295–4306 (2022). https://doi.org/10.1038/s41388-022-02428-1
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DOI: https://doi.org/10.1038/s41388-022-02428-1
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