Omics · study · 2026
Super-enhancers reorganization controls re-sensitization of oxaliplatin-resistant FBXW7-mutated colorectal cancer
Listed in NCBI GEO
Epigenetic plasticity and large-scale chromatin remodeling characterize tumor evolution and the emergence of subclones resistant to conventional therapies.
Description
Catalytically inactive class IIa HDACs (HDAC4, HDAC5, HDAC7, HDAC9) act as acetyl-lysine readers that form the scaffold for the targeted recruitment of chromatin remodeling complexes, making them very attractive therapeutic targets in the field of oncology. In this study, we found that HDAC4 is proteasomal degraded in cancer cells impaired in DNA repair by homologous recombination.
Genetic screening identified FBXW7 as the E3 ligase responsible for this degradation. FBXW7 loss-of-function (LOF) mutations are frequently found in patients with colorectal cancer (CRC), and FBXW7 mutation status is associated with the development of resistance to oxaliplatin. Deletion of HDAC4 or its forced degradation with a PROTAC-based compound restored Oxaliplatin sensitivity in FBXW7-mutated CRC cells, patient-derived organoids (PDOs) and xenografts, with no effect on DNA damage response activation or DNA platination.
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Mechanistically, forced removal of HDAC4 in FBXW7-mutant CRC cells and PDOs treated with Oxaliplatin resulted in a deep rearrangement of the super-enhancer landscape, with a dramatic loss of super-enhancers found in Oxaliplatin-resistant samples and restoration of defined super-enhancers found in Oxaliplatin-sensitive cells. The pharmacological disassembly of HDAC4 complexes partially recapitulated the effects obtained with the PROTAC-based HDAC4 compound, demonstrating the importance of the epigenetic function of HDAC4 in supporting drug resistance.
This study supports HDAC4 as a key mediator of Oxaliplatin resistance in FBXW7-mutated CRC and highlights the remodeling of a well-defined repertoire of super-enhancers as part of the process of successful re-sensitization.
Links
Get the data
- GEO FTP directory ftp.ncbi.nlm.nih.gov/geo/series/GSE270nnn/GSE270840 ↗
download · from NCBI GEO
Where it is published
- GEO accession page ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE270840 ↗
landing page · from NCBI GEO
Documentation and papers
- PRJNA1128608 ncbi.nlm.nih.gov/bioproject/PRJNA1128608 ↗
project · from NCBI GEO
- PubMed 41174352 pubmed.ncbi.nlm.nih.gov/41174352 ↗
publication · from NCBI GEO
Topics
- Stated by source
- Genome binding/occupancy profiling by high throughput sequencing · Homo sapiens
- From keywords
- Life Sciences
- Inferred from text
- Cancer 75%
Provenance · 1 source records, 8 field assertions
| Source | Key | Last seen | Raw |
|---|---|---|---|
| NCBI GEO | GSE270840 | 12 d ago | JSON v1 |
| Field | Assertion | Extractor | Evidence |
|---|---|---|---|
| access_level | source · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| concepts[disease].local:disease:cancer | enrichment · NCBI GEO | keyword-concept-rules@1.0.0 | title+description (75%) |
| concepts[field].local:field:life-sciences | mapping · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| concepts[method].geo_series_type:genome-binding-occupancy-profiling-by-high-throughput-sequencing | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /gdstype |
| concepts[organism].NCBITaxon:9606 | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /taxon |
| description | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /summary |
| publication_date | source · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| title | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /title |