Omics · study · 2026
Molecule Glue That Stabilizes the LRPPRC-MET-G4 Interaction Complex to Drive MET Downregulation
Listed in NCBI GEO
Targeting the MET oncoprotein is an effective strategy in precision cancer therapy, whereas its clinical efficacy varies dramatically across tumor types.
Description
To address this challenge, we explored an alternative approach to downregulate MET expression at transcriptional levels. We identified a cis-regulatory element in the MET proximal promoter region that folds into a stable parallel DNA G-quadruplex (MET-G4).
We further determined the high-resolution NMR solution structure of MET-G4 and demonstrated that MET-G4 recruits the cellular LRPPRC protein to promote MET transcription, thereby uncovering a previously unrecognized epigenetic mechanism that drives MET overexpression. Moreover, we characterized the specific G4-binding domain of LRPPRC and elucidated its structural basis for recognition of the MET-G4. Through screening an in-house natural product library, we identified nitidine alkaloid (NIT) as a potent MET-G4 stabilizer.
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Strikingly, nitidine acts as a molecular glue, strengthening the LRPPRC-MET-G4 interaction and inducing the formation of a stable LRPPRC-NIT-MET-G4 ternary complex. This complex likely alters the structure and function of LRPPRC, ultimately leading to MET downregulation and potent anticancer effects. Notably, this is the first report of a molecular glue that stabilizes a G4-protein complex to silence an oncogene.
Additionally, comprehensive in vitro and in vivo experiments demonstrated that nitidine significantly inhibits tumor progression mainly through an LRPPRC-MET-G4-dependent mechanism. Collectively, our study reveals a novel epigenetic regulatory mechanism involving LRPPRC-MET-G4-mediated MET upregulation and suggests a promising therapeutic strategy for MET-driven tumors with molecular glues that target the LRPPRC-MET-G4 interface
Links
Get the data
- GEO FTP directory ftp.ncbi.nlm.nih.gov/geo/series/GSE330nnn/GSE330177 ↗
download · from NCBI GEO
Where it is published
- GEO accession page ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE330177 ↗
landing page · from NCBI GEO
Documentation and papers
- PRJNA1462468 ncbi.nlm.nih.gov/bioproject/PRJNA1462468 ↗
project · from NCBI GEO
- PubMed 42243089 pubmed.ncbi.nlm.nih.gov/42243089 ↗
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 | GSE330177 | 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 |