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Megacomplex protects ESR1 from degradation by Fulvestrant in epithelial ovarian cancer

GSE267459 Homo sapiens (human) ChIP-seq / ATAC-seq (genome binding and open chromatin) 16 samples Submitted 2025/05/15 Platform GPL24676
At a glance

ChIP-seq / ATAC-seq (genome binding and open chromatin) · human · 16 samples

What it is
ChIP-seq / ATAC-seq (genome binding and open chromatin)Where proteins bind the genome, or which regions are open and active.
Organism
Homo sapiens (human)
Topic
Ovarian cancerThis series is part of our curated briefing on it.
Samples
16 samples: 16 samples, each with a distinct title — no replicated groupsGroups are read from the sample names, not from the paper. Check the list below.
Data you can get
A processed table (series matrix) and supplementary files from NCBI; the raw sequencing reads from ENA. Which of these hold counts depends on the study, so check the file list.
Paper
The Megacomplex protects ER-alpha from degradation by Fulvestrant in epithelial ovarian cancerCancer letters · 2025
Summary (written by the submitters)
Ovarian cancer, a significant contributor to cancer-related mortality, often exhibits limited responsiveness to hormonal therapies targeting the estrogen receptor (ESR1). This study aimed to elucidate the mechanisms behind ESR1 resistance to the therapeutic drug Fulvestrant (ICI182780 or ICI). We identified a 1.3MDa Megacomplex comprising ESR1, FOXA1, and PITX1 using size exclusion chromatography.
Read the full summary ↓
These factors showed colocalized binding at 6,775 genomic positions in the ovarian cancer cell line, PEO4, including important super-enhancers. Notably, compared to the cytoplasmic version, nuclear ESR1 was minimally degraded by ICI, suggesting a mechanism for drug resistance via the protective confines of the Megacomplex. Combining a small molecule inhibitor of active chromatin and super-enhancers, JQ1, with ICI significantly enhanced ESR1 degradation, especially within the Megacomplex. Molecular analysis showed that this combination disrupted the cyto-nuclear ESR1 shuttling responsible for tumor cell proliferation. Pathway enrichment analysis of RNAseq gene sets following Estradiol, ICI, or ICI plus JQ1 treatments paralleled pathway enrichment found from target genes of Megacomplex binding identified through ChIPseq. Mass-spec analysis revealed that proteins within the Megacomplex macromolecule also produced similar pathway enrichments after modulation by Estradiol or ICI. Each of these findings independently implicates Megacomplex in ESR1-driven ovarian cancer chromatin regulation. Moreover, this combined treatment strategy exhibited superior inhibition of cell proliferation and viability compared to ICI alone. Other cell lines, PEO1, OVCAR4, OVCAR8, and the normal ovarian cell line, T1074, substantiated the specificity of the response. By uncovering ESR1's resistance within the Megacomplex, the combined ICI plus JQ1 treatment elucidates a novel drug treatment vulnerability.
Published in
The Megacomplex protects ER-alpha from degradation by Fulvestrant in epithelial ovarian cancer
Jaiswal SK, Fedkenheuer K, Khamar R et al. · Cancer letters 2025 · PMID 39048045 · doi:10.1016/j.canlet.2024.217129
This dataset
Open GSE267459 in finder → Find more human ChIP / ATAC / CUT&Tag datasets → Ovarian cancer landscape →
Download · which file do I need?

Direct links to NCBI and ENA, no account and no request form. Pick by what you want to do: take the small processed table to look, the supplementary files to re-analyse, or the original raw data to start over.

1 · Just have a look

Processed table

The series matrix: one table of values per sample as the submitters processed it. The smallest download, and it opens in Excel or R. Start here to see what the data look like.

Series matrix ↓
2 · Re-analyse it

Supplementary files

The count tables and other files the authors uploaded. Take only the samples you need, or the whole study as GSE267459_RAW.tar (it can run to tens of gigabytes).

All supplementary files ↗ Whole study · RAW.tar ↓
3 · Start from the raw reads

Raw sequencing reads

The original FASTQ files, straight from the sequencer, held at ENA. Large, and you align them yourself, so only choose this if you need to re-process the study from scratch.

Raw reads on ENA ↗

What the files usually look like: Look for peak files (.bed, .narrowPeak) and signal tracks (.bigWig) among the supplementary files; the raw reads are on ENA.

Also filed as BioProject PRJNA1111537 and SRA study SRP507644. Searching any of these in the dataset finder brings you back here.

NCBI GEO page ↗ Paper (PMID 39048045) ↗
Study design
16 samples, each with a distinct title — no replicated groups

Any grouping that defines a comparison lives in the sample characteristics, which GEO records separately from the titles.

How we read this: Read from 16 sample titles: 16 distinct titles with little repetition. These groups are guessed from the sample names, not taken from the paper, so check them against the sample list below before relying on them.

Samples in this study
More Ovarian cancer datasets

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