GEO series

NSD2 is a requisite subunit of the AR/FOXA1 neo-enhanceosome in promoting prostate tumorigenesis [ChIP-seq]

GSE242734 Homo sapiens (human) ChIP-seq / ATAC-seq (genome binding and open chromatin) 12 samples Submitted 2024/03/20 Platform GPL16791

At a glance

ChIP-seq / ATAC-seq (genome binding and open chromatin) · human · 12 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)
Samples: 12 samples: 12 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: NSD2 is a requisite subunit of the AR/FOXA1 neo-enhanceosome in promoting prostate tumorigenesisbioRxiv : the preprint server for biology · 2024

Summary (written by the submitters)

Androgen receptor (AR) is a ligand-responsive transcription factor that binds at enhancers to drive terminal differentiation of the prostatic luminal epithelia. By contrast, in tumors originating from these cells, AR chromatin occupancy is extensively reprogrammed to drive hyper-proliferative, metastatic, or therapy-resistant phenotypes, the molecular mechanisms of which remain poorly understood.

Read the full summary ↓

Here we show that the tumor-specific enhancer circuitry of AR is critically reliant on the activity of Nuclear Receptor Binding SET Domain Protein 2 (NSD2), a histone 3 lysine 36 di-methyltransferase. NSD2 is ectopically expressed in prostate cancer cells and catalytic inhibition of NSD2 impairs AR trans-activation potential through partial off-loading from over 40,000 genomic sites or greater than 65% of its cistrome. The NSD2-dependent AR sites distinctly harbor a chimeric AR-half motif juxtaposed to a FOXA1 element. Similar chimeric motifs of AR are absent at the NSD2-independent AR enhancers and contain the canonical palindromic motifs instead. Meta-analyses of AR cistromes from patient tumors uncovered chimeric AR motifs to exclusively participate in tumor-specific enhancer circuitries, with a minimal role in physiological activity of AR. Accordingly, NSD2 inactivation attenuated hallmark cancer phenotypes that were fully reinstated upon exogenous NSD2 re-expression. Inactivation of NSD2 also engendered increased dependency on its paralog NSD1, which independently maintained AR and MYC hyper-transcriptional programs in cancer cells. Therapeutically exploiting these insights, we developed a dual NSD1/2 PROTAC degrader, called LLC0150, which was preferentially cytotoxic in AR-dependent prostate cancer and synergized with enzalutamide. In a pan-cancer screen, comprising over 120 cell lines from 22 distinct lineages, NSD1/2 co-degradation triggered apoptotic cell death in AR-addicted prostate cancer as well as NSD2-altered hematologic malignancies. Altogether, we identify NSD2 as a novel subunit of the AR neo-enhanceosome that wires prostate cancer gene expression programs, positioning NSD1/2 paralog co-targeting as a novel and potent therapeutic strategy.

Published in

NSD2 is a requisite subunit of the AR/FOXA1 neo-enhanceosome in promoting prostate tumorigenesis

Parolia A, Eyunni S, Verma BK et al. · bioRxiv : the preprint server for biology 2024 · PMID 38464251 · doi:10.1101/2024.02.22.581560

This dataset

Open GSE242734 in finder → Find more human ChIP / ATAC / CUT&Tag datasets →

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 GSE242734_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 PRJNA1014432 and SRA study SRP459323. Searching any of these in the dataset finder brings you back here.

NCBI GEO page ↗ Paper (PMID 38464251) ↗

Study design

12 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 12 sample titles: 12 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

GSM7767862 LNCaP_AR_NSD2KO
GSM7767863 LNCaP_AR_NSD2WT
GSM7767864 LNCaP_FOXA1_NSD2KO
GSM7767865 LNCaP_FOXA1_NSD2WT
GSM7767866 LNCaP_H3k27Ac_NSD2KO
GSM7767867 LNCaP_H3k27Ac_NSD2WT
GSM7767868 LNCaP_AR_DMSO
GSM7767869 LNCaP_AR_LLC0150
GSM7767870 LNCaP_FOXA1_DMSO
GSM7767871 LNCaP_FOXA1_LLC0150
GSM7767872 LNCaP_H3K27Ac_DMSO
GSM7767873 LNCaP_H3K27Ac_LLC0150

Datasets on a similar topic

GSE242737 NSD2 is a requisite subunit of the AR/FOXA1 neo-enhanceosome in promoting prostate tumorigenesis 44 samples shares foxa1, nsd2, neo-enhanceosome, tumorigenesis, requisite, promoting, prostate
GSE242735 NSD2 is a requisite subunit of the AR/FOXA1 neo-enhanceosome in promoting prostate tumorigenesis [RNA-seq] 32 samples shares foxa1, nsd2, neo-enhanceosome, tumorigenesis, requisite, promoting, prostate
GSE245967 EP300/CREBBP acetyltransferase inhibition limits steroid receptor and FOXA1 signaling in prostate cancer cells (ChIP-seq) 90 samples shares foxa1, prostate, chip-seq
GSE281784 Targeting FOXA1 and FOXA2 Disrupts the Lineage-Specific Oncogenic Output in Prostate Cancer [ChIP-seq] 67 samples shares foxa1, prostate, chip-seq
GSE285790 KMT2D promotes castration-resistant prostate cancer progerssion by reactivating AR via FOXA1 [ChIP-seq, Cut & Tag] 48 samples shares foxa1, prostate, chip-seq
GSE248629 Epigenetic Activation and alteration of chromatin structure regulated by NSD2 in metastatic castration-resistant prostate cancer (ChIP-seq) 15 samples shares nsd2, prostate, chip-seq
GSE245966 EP300/CREBBP acetyltransferase inhibition limits steroid receptor and FOXA1 signaling in prostate cancer cells (ATAC-seq) 32 samples shares foxa1, prostate
GSE305432 FOXA1/FOXM1 ChIP-seq on giredestrant-resistant ER+ breast cancer cell lines 20 samples shares foxa1, chip-seq

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