The Journal of Practical Medicine >

2025 , Vol. 41 >Issue 18: 2796 - 2805

DOI: https://doi.org/10.3969/j.issn.1006-5725.2025.18.003

Feature Reports：Breast carcinoma

Super⁃enhancer⁃mediated GSE1 activation drives breast cancer proliferation through Wnt/β⁃catenin signaling

  • Peijing DU ,
  • Enxi HU ,
  • Xiang TAO ,
  • Jia CAO ,
  • Libin WANG
Expand
  • *.Ningxia Medical University General Hospital，Yinchuan 750004，Ningxia，China
    *.The First Clinical Medical College of Ningxia Medical University，Yinchuan 750004，Ningxia，China

Received date: 2025-05-16

  Online published: 2025-09-25

Fold

Abstract

Objective To investigate the molecular mechanism by which super enhancers （SEs） regulate the expression of the genetic suppressor element 1 （GSE1） and influence the proliferation of breast cancer cell line MCF-7. Methods The oncogene GSE1， driven by SEs， was identified through analysis of the ChIP-seq dataset of MCF-7 cells obtained from the GEO database. The protein expression level of GSE1 was assessed via Western blot following treatment with the bromodomain-containing protein 4 （BRD4） inhibitor JQ1. The expression of GSE1 across various cancers and different breast cancer subtypes was analyzed using the Human Protein Atlas （HPA） and The Cancer Genome Atlas （TCGA） databases， respectively. Overall survival （OS） of breast cancer patients was compared between the GSE1 high-expression and low-expression groups using the GEPIA database. Immunohistochemistry （IHC） was performed to evaluate GSE1 expression in breast cancer tissue samples. The mRNA expression levels of GSE1 in different breast cancer cell lines were validated by RT-qPCR. A GSE1 interference vector was constructed and transfected into MCF-7 cells， and the knockdown efficiency was assessed using Western blot. Cell proliferation and migration were evaluated using CCK-8 assay， colony formation assay， wound healing assay， and Transwell migration assay. Potential GSE1-interacting proteins were predicted using the STRING database. Finally， Western blot analysis was conducted to assess changes in epithelial-mesenchymal transition （EMT）-related proteins and key components of the Wnt/β-catenin signaling pathway. Results The integrative genomics viewer （IGV） was used to visualize ChIP-seq data from MCF-7 cells， and the rank ordering of super enhancers （ROSE） algorithm was applied to predict the SE region of GSE1 in the MCF-7 genome. GSE1 and BRD4 expression levels were significantly reduced following JQ1 treatment （P < 0.05）. High expression levels of GSE1 in breast cancer were confirmed through analyses using the HPA， TCGA， and GEPIA databases， as well as IHC， and these findings were associated with poor prognostic outcomes in breast cancer patients （P < 0.05）. RT-qPCR results further demonstrated that GSE1 is significantly upregulated in breast cancer cells （P < 0.05）. Analysis of the STRING database revealed a strong correlation between GSE1 and Snail （Snai1）. Transfection of a GSE1-specific interference vector significantly inhibited the proliferation and migration of MCF-7 cells compared to the control group， upregulated E-cadherin and Occludin expression， and downregulated N-cadherin and Snail expression （P < 0.05）. Additionally， knockdown of GSE1 resulted in decreased expression of Wnt/β-catenin signaling pathway-related proteins， including β-catenin， Wnt-5a， and Cyclin-D1， along with increased Axin1 expression （P < 0.05）. Conclusion SE driven GSE1 promotes the proliferation， migration and EMT of MCF-7 cells via the Wnt/β-catenin signaling pathway.

Key words： super-enhancer; GSE1; epithelial-mesenchymal transition; proliferation; migration; Wnt/β-catenin signaling pathway

Cite this article

Peijing DU , Enxi HU , Xiang TAO , Jia CAO , Libin WANG . Super⁃enhancer⁃mediated GSE1 activation drives breast cancer proliferation through Wnt/β⁃catenin signaling[J]. The Journal of Practical Medicine, 2025 , 41(18) : 2796 -2805 . DOI: 10.3969/j.issn.1006-5725.2025.18.003

References

[1] BENITEZ FUENTES J D， MORGAN E， DE LUNA AGUILAR A， et al. Global stage distribution of breast cancer at diagnosis： A systematic review and meta-analysis［J］. JAMA Oncol， 2024， 10（1）： 71-78. doi:10.1001/jamaoncol.2023.4837
[2] 邓雅倩， 李文肖， 徐泽林， 等. 生长方位量化联合S-Detect技术对乳腺癌腋窝淋巴结转移的预测价值［J］. 实用医学杂志， 2025， 41（1）： 100-107.
[3] 刘芬， 赵辉， 郭利敏. 多组学联合检测对乳腺癌临床病理特征、新辅助化疗效果的评估效能［J］. 实用医学杂志， 2024， 40（24）： 3539-3546.
[4] POTT S， LIEB J D. What are super-enhancers？［J］. Nat Genet， 2015， 47（1）： 8-12. doi:10.1038/ng.3167
[5] HNISZ D， ABRAHAM B J， LEE T I， et al. Super-enhancers in the control of cell identity and disease［J］. Cell， 2013， 155（4）： 934-947. doi:10.1016/j.cell.2013.09.053
[6] SIM N， CARTER J M， DEKA K， et al. TWEAK/Fn14 signaling driven super-enhancer reprogramming promotes pro-metastatic metabolic rewiring in triple-negative breast cancer［J］. Nat Commun， 2024， 15（1）： 5638. doi:10.1038/s41467-024-50071-z
[7] QIAN H， ZHU M， TAN X， et al. Super-enhancers and the super-enhancer reader BRD4： Tumorigenic factors and therapeutic targets［J］. Cell Death Discov， 2023， 9（1）： 470. doi:10.1038/s41420-023-01775-6
[8] ZHENG Z Z， XIA L， HU G S， et al. Super-enhancer-controlled positive feedback loop BRD4/ERα-RET-ERα promotes ERα-positive breast cancer［J］. Nucleic Acids Res， 2022， 50（18）： 10230-10248. doi:10.1093/nar/gkac778
[9] CHEN C H， YANG N， ZHANG Y， et al. Inhibition of super enhancer downregulates the expression of KLF5 in basal-like breast cancers［J］. Int J Biol Sci， 2019， 15（8）： 1733-1742. doi:10.7150/ijbs.35138
[10] BAMODU O A， WANG Y H， HO C H， et al. Genetic suppressor element 1 （GSE1） promotes the oncogenic and recurrent phenotypes of castration-resistant prostate cancer by targeting tumor-associated calcium signal transducer 2 （TACSTD2）［J］. Cancers， 2021， 13（16）： 3959. doi:10.3390/cancers13163959
[11] WANG W， WANG S， XU A M， et al. Overexpression of GSE1 related to trastuzumab resistance in gastric cancer cells［J］. Biomed Res Int， 2021， 2021（1）： 8834923. doi:10.1155/2021/8834923
[12] DEBNATH P， HUIREM R S， DUTTA P， et al. Epithelial-mesenchymal transition and its transcription factors［J］. Biosci Rep， 2022， 42（1）： BSR20211754. doi:10.1042/bsr20211754
[13] FONTANA R， MESTRE-FARRERA A， YANG J. Update on epithelial-mesenchymal plasticity in cancer progression［J］. Annu Rev Pathol， 2024， 19（1）： 133-156. doi:10.1146/annurev-pathmechdis-051222-122423
[14] HASHEMI M， ARANI H Z， OROUEI S， et al. EMT mechanism in breast cancer metastasis and drug resistance： Revisiting molecular interactions and biological functions［J］. Biomed Pharmacother， 2022， 155： 113774. doi:10.1016/j.biopha.2022.113774
[15] PARSONS M J， TAMMELA T， DOW L E. WNT as a driver and dependency in cancer［J］. Cancer Discov， 2021， 11（10）： 2413-2429. doi:10.1158/2159-8290.cd-21-0190
[16] RIM E Y， CLEVERS H， NUSSE R. The wnt pathway： From signaling mechanisms to synthetic modulators［J］. Annu Rev Biochem， 2022， 91（1）： 571-598. doi:10.1146/annurev-biochem-040320-103615
[17] YAN R， CHEN T. SLC35A2 is a novel prognostic biomarker and promotes cell proliferation and metastasis via wnt/β-catenin/EMT signaling pathway in breast cancer［J］. Sci Rep， 2025， 15（1）： 130. doi:10.1038/s41598-024-84584-w
[18] JIA Q， CHEN S， TAN Y， et al. Oncogenic super-enhancer formation in tumorigenesis and its molecular mechanisms［J］. Exp Mol Med， 2020， 52（5）： 713-723. doi:10.1038/s12276-020-0428-7
[19] XI Y， WANG R， QU M， et al. Super-enhancer-hijacking RBBP7 potentiates metastasis and stemness of breast cancer via recruiting NuRD complex subunit LSD1［J］. J Transl Med， 2025， 23（1）： 266. doi:10.1186/s12967-025-06270-3
[20] NICOSIA L， BOFFO F L， CECCACCI E， et al. Pharmacological inhibition of LSD1 triggers myeloid differentiation by targeting GSE1 oncogenic functions in AML［J］. Oncogene， 2022， 41（6）： 878-894. doi:10.1038/s41388-021-02123-7
[21] CHAI P， TIAN J， ZHAO D， et al. GSE1 negative regulation by miR-489-5p promotes breast cancer cell proliferation and invasion［J］. Biochem Biophys Res Commun， 2016， 471（1）： 123-128. doi:10.1016/j.bbrc.2016.01.168
[22] MANFIOLETTI G， FEDELE M. Epithelial–mesenchymal transition （EMT） 2021［J］. Int J Mol Sci， 2022， 23（10）： 5848. doi:10.3390/ijms23105848
[23] XU X， ZHANG M， XU F， et al. Wnt signaling in breast cancer： Biological mechanisms， challenges and opportunities［J］. Mol Cancer， 2020， 19（1）： 165. doi:10.1186/s12943-020-01276-5
[24] SONG P， GAO Z， BAO Y， et al. Wnt/β-catenin signaling pathway in carcinogenesis and cancer therapy［J］. J Hematol Oncol， 2024， 17（1）： 46. doi:10.1186/s13045-024-01563-4
[25] ZHANG Y， WANG X. Targeting the wnt/β-catenin signaling pathway in cancer［J］. J Hematol Oncol， 2020， 13（1）： 165. doi:10.1186/s13045-020-00990-3
[26] 肖知周， 黄莺， 卞华伟. 基于Wnt/β-catenin信号通路介导的自噬和凋亡探讨苦豆子碱对骨质疏松小鼠骨代谢的影响［J］.实用医学杂志， 2025， 41（4）： 500-508.
[27] SUN L， XING J， ZHOU X， et al. Wnt/β-catenin signaling， epithelial-mesenchymal transition and crosslink signaling in colorectal cancer cells［J］. Biomed Pharmacother， 2024， 175： 116685. doi:10.1016/j.biopha.2024.116685
[28] ZHU L， TIAN Q， GAO H， et al. PROX1 promotes breast cancer invasion and metastasis through WNT/β-catenin pathway via interacting with hnRNPK［J］. Int J Biol Sci， 2022， 18（5）： 2032-2046. doi:10.7150/ijbs.68960
Options
Outlines

/

〈 〉