1. Academic Validation
  2. The PRC2 complex epigenetically silences GATA4 to suppress cellular senescence and promote the progression of breast cancer

The PRC2 complex epigenetically silences GATA4 to suppress cellular senescence and promote the progression of breast cancer

  • Transl Oncol. 2024 Aug:46:102014. doi: 10.1016/j.tranon.2024.102014.
Wenqian Yu 1 Xiaona Lin 2 Shuai Leng 1 Yiming Hou 1 Zhiqiao Dang 1 Shishan Xue 1 Na Li 3 Fengquan Zhang 4
Affiliations

Affiliations

  • 1 Research Center of Translational Medicine, Department of Cardiac Surgery, Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250013, China.
  • 2 Department of Cardiovascular Surgery, Shandong Second Provincial General Hospital, Jinan, Shandong 250022, China.
  • 3 Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial ENT Hospital, Shandong University, No. 4, Duanxin West Road, Jinan, Shandong 250022, China; Center of Clinical Laboratory, Shandong Second Provincial General Hospital, Jinan, Shandong 250022, China. Electronic address: linda831223@163.com.
  • 4 Research Center of Translational Medicine, Department of Cardiac Surgery, Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250013, China. Electronic address: zhangfengquan76@163.com.
Abstract

Background: The transcription factor GATA4 is pivotal in Cancer development but is often silenced through mechanisms like DNA methylation and histone modifications. This silencing suppresses the transcriptional activity of GATA4, disrupting its normal functions and promoting Cancer progression. However, the precise molecular mechanisms and implications of GATA4 silencing in tumorigenesis remain unclear. Here, we aim to elucidate the mechanisms underlying GATA4 silencing and explore its role in breast Cancer progression and its potential as a therapeutic target.

Methods: The GATA4-breast Cancer prognosis link was explored via bioinformatics analyses, with GATA4 expression measured in breast tissues. Functional gain/loss experiments were performed to gauge GATA4's impact on breast Cancer cell malignancy. GATA4-PRC2 complex interaction was analyzed using silver staining and mass spectrometry. Chromatin immunoprecipitation, coupled with high-throughput Sequencing, was used to identify GATA4-regulated downstream target genes. The in vitro findings were validated in an in situ breast Cancer xenograft mouse model.

Results: GATA4 mutation and different breast Cancer subtypes were correlated, suggesting its involvement in disease progression. GATA4 suppressed cell proliferation, invasion, and migration while inducing Apoptosis and senescence in breast Cancer cells. The GATA4-PRC2 complex interaction silenced GATA4 expression, which altered the regulation of FAS, a GATA4 downstream gene. In vivo experiments verified that GATA4 inhibits tumor growth, suggesting its regulatory function in tumorigenesis.

Conclusions: This comprehensive study highlights the epigenetic regulation of GATA4 and its impact on breast Cancer development, highlighting the PRC2-GATA4-FAS pathway as a potential target for therapeutic interventions in breast cancers.

Keywords

Breast cancer; Cell senescence; Epigenetic regulation; GATA4; PRC2 complex.

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