GRHL2-controlled gene expression networks in luminal breast cancer

Abstract

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.

Placental co-transcriptional activator Vestigial-like 1 (VGLL1) drives tumorigenesis via increasing transcription of proliferation and invasion genes

“…Our results validated these findings and expanded the list of TFs that VGLL1 can potentially interact with to include TEAD2, TEAD3, RUNX2, GATA6, AP-1 and GRHL2. These TFs have been linked to the hippo pathway and epithelial tissue development, PI3K/AKT pathway activation, and the promotion of tumorigenesis ( 49 – 51 ). Notably, we found that VGLL1 bound mostly at intron regions.…”

Ovulatory signal-triggered chromatin remodeling in ovarian granulosa cells by HDAC2 phosphorylation activation-mediated histone deacetylation

“…TBP is a critical transcription factor required for promoter recognition and assembly of transcription pre-initiation complexes [ 38 ]. GRHL2 acts as an essential transcription factor for epithelial-to-mesenchymal transitions and estrogen-induced transcription in breast cancer [ 39 , 40 ]. A recent study showed that H3K27Ac-enriched genes harbor a putative GRHL transcription factor-binding site in psoriasis [ 41 ].…”

Cancer cell plasticity: from cellular, molecular, and genetic mechanisms to tumor heterogeneity and drug resistance

“…These factors bolster epithelial attributes in both normal and neoplastic cells, chiefly by repressing the transcription of mesenchymal markers and establishing reciprocal inhibitory loops with EMT-TFs [66][67][68][69]. In addition to their regulatory roles, several MET-TFs, including CDH1, ZO-1, and those encoding claudin-4 and claudin-5 (CLDN4 and CLDN5), directly stimulate the transcription of genes that codify proteins essential for epithelial lineage specification [70,71]. These orchestrated molecular events underscore the complexity of cellular transitions during EMT and MET, highlighting the necessity for a nuanced understanding of these processes in both health and disease.…”