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Rhein suppresses esophageal cancer development by regulating cell cycle through DNMT3B gene

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Abstract

The mechanism by which DNMT3B facilitates esophageal cancer (ESCA) progression is currently unknown, despite its association with adverse prognoses in several cancer types. To investigate the potential therapeutic effects of the Chinese herbal medicine rhubarb on esophageal cancer (ESCA), we adopted an integrated bioinformatics approach. Gene Set Enrichment Analysis (GSEA) was first utilized to screen active anti-ESCA components in rhubarb. We then employed Weighted Gene Co-expression Network Analysis (WGCNA) to identify key molecular modules and targets related to the active components and ESCA pathogenesis. This system-level strategy integrating multi-omics data provides a powerful means to unravel the molecular mechanisms underlying the anticancer activities of natural products, like rhubarb. To investigate module gene functional enrichment, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted. In addition, we evaluated the predictive impact of DNMT3B expression on ESCA patients utilizing the Kaplan–Meier method. Finally, we conducted experiments on cell proliferation and the cell cycle to explore the biological roles of DNMT3B. In this study, we identified Rhein as the main active ingredient of rhubarb that exhibited significant anti-ESCA activity. Rhein markedly suppressed ESCA cell proliferation. Utilizing Weighted Gene Co-expression Network Analysis (WGCNA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, we determined that the blue module was associated with Rhein target genes and the cell cycle. Additionally, DNMT3B was identified as a Rhein target gene. Analysis of The Cancer Genome Atlas (TCGA) database revealed that higher DNMT3B levels were associated with poor prognosis in ESCA patients. Furthermore, Rhein partially reversed the overexpression of DNMT3B to inhibit ESCA cell proliferation. In vitro studies demonstrated that Rhein and DNMT3B inhibition disrupted the S phase of the cell cycle and affected the production of cell cycle-related proteins. In this study, we found that Rhein exerts its anti-proliferative effects in ESCA cells by targeting DNMT3B and regulating the cell cycle.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

This study was supported by Research project of Health Commission of Heilongjiang Province (Grant number 20221313050598). In addition, the authors would like to thank The Third Affiliated Hospital of Qiqihar Medical University for their support in conducting the experiments and data analysis. We also appreciate the help of The Third Affiliated Hospital of Qiqihar Medical University in editing the manuscript.

Funding

Research project of Health Commission of Heilongjiang Province (Grant Number 20221313050598).

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Authors and Affiliations

  1. Department of Pharmacy, The Third Affiliated Hospital of Qiqihar Medical University, 3 Tai Shun Street, Tiefeng District, Qiqihar City, Heilongjiang Province, China

    Cheng Li, Jingjing Yu, Ying Feng, Xiaoxue Sun, Mingming Sun, Weihui Ni, Jun Shao & Baoxin Wang

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  1. Cheng Li
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  2. Jingjing Yu
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  4. Xiaoxue Sun
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  7. Jun Shao
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  8. Baoxin Wang
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Contributions

C.L. provided study materials and patients. B.X.W. conceived and designed the manuscript. W.H.N. provided administrative support. J.J.Y. collected and curated the data. Y.F. analyzed and interpreted the data. X.X.S., M.M.S., and J.S. wrote the main manuscript text. All authors approved the manuscript.

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Correspondence to Baoxin Wang.

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Li, C., Yu, J., Feng, Y. et al. Rhein suppresses esophageal cancer development by regulating cell cycle through DNMT3B gene. Med Oncol 41, 153 (2024). https://doi.org/10.1007/s12032-024-02359-9

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