GRHL2-controlled gene expression networks in luminal breast cancer

Cell Communication and Signaling

Research

Haoyu Wu¹  Lucia Daxinger¹  Jihed Chouaref¹  Marcel Smid²  John W. M. Martens²  Michelle T. Paulsen³  Mats Ljungman³  Zi Wang⁴  Erik H. J. Danen⁴  Bircan Coban⁴ 

[1] Department of Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands;Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands;Departments of Radiation Oncology and Environmental Health Sciences, University of Michigan Medical School, Ann Arbor, MI, USA;Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands;

关键词: Breast cancer;    Luminal;    GRHL2;    CHIP-seq;    BRU-seq;    Transcription;    Gene regulation;   

DOI  :  10.1186/s12964-022-01029-5

 received in 2022-11-09, accepted in 2022-12-24,  发布年份 2022

来源: Springer

【 摘 要 】

Grainyhead like 2 (GRHL2) is an essential transcription factor for development and function of epithelial tissues. It has dual roles in cancer by supporting tumor growth while suppressing epithelial to mesenchymal transitions (EMT). GRHL2 cooperates with androgen and estrogen receptors (ER) to regulate gene expression. We explore genome wide GRHL2 binding sites conserved in three ER⍺/GRHL2 positive luminal breast cancer cell lines by ChIP-Seq. Interaction with the ER⍺/FOXA1/GATA3 complex is observed, however, only for a minor fraction of conserved GRHL2 peaks. We determine genome wide transcriptional dynamics in response to loss of GRHL2 by nascent RNA Bru-seq using an MCF7 conditional knockout model. Integration of ChIP- and Bru-seq pinpoints candidate direct GRHL2 target genes in luminal breast cancer. Multiple connections between GRHL2 and proliferation are uncovered, including transcriptional activation of ETS and E2F transcription factors. Among EMT-related genes, direct regulation of CLDN4 is corroborated but several targets identified in other cells (including CDH1 and ZEB1) are ruled out by both ChIP- and Bru-seq as being directly controlled by GRHL2 in luminal breast cancer cells. Gene clusters correlating positively (including known GRHL2 targets such as ErbB3, CLDN4/7) or negatively (including TGFB1 and TGFBR2) with GRHL2 in the MCF7 knockout model, display similar correlation with GRHL2 in ER positive as well as ER negative breast cancer patients. Altogether, this study uncovers gene sets regulated directly or indirectly by GRHL2 in luminal breast cancer, identifies novel GRHL2-regulated genes, and points to distinct GRHL2 regulation of EMT in luminal breast cancer cells.6_BaCm7NaLGTK4K5qg2XWLVideo Abstract

【 授权许可】

CC BY   
© The Author(s) 2023

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