SETD2 Loss Creates A Permissive Epigenetic Landscape that Promotes Kidney Cancer Metastasis and Engenders Therapeutic Vulnerabilities
UID: 10931
- Description
- Summary from GEO:
"SETD2, a H3K36 trimethyltransferase, is frequently mutated in human cancers with the highest prevalence (13%) in clear cell renal cell carcinoma (ccRCC). Genomic profiling of primary ccRCC tumors reveals a positive correlation between SETD2 mutations and metastasis. However, whether and how SETD2-loss promotes metastasis remains unclear. Here, we detected SETD2 mutations in 24 of 51 (47%) metastatic ccRCC tumors. Using SETD2-mutant metastatic ccRCC patient-derived cell line and xenograft models, we showed that H3K36me3 restoration greatly reduced distant metastases of ccRCC in mice. An integrated ATAC-seq, ChIP-seq, and transcriptome analysis concluded a tumor suppressor model in which loss of SETD2-mediated H3K36me3 activates enhancers to drive oncogenic transcription through dysregulating histone chaperone recruitment, enhancing histone exchange, and expanding chromatin accessibility. Furthermore, we uncovered mechanism-based therapeutic strategies for SETD2-deficient cancer through inhibition of histone chaperones. Overall, SETD2-loss creates a permissive epigenetic landscape for cooperating oncogenic drivers to amplify transcriptional output, providing unique therapeutic opportunities."
Overall design: Refer to individual data subseries in GEO
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Access via GEO
Accession #: GSE146583Access via BioProject
Accession #: PRJNA610874 - Access Restrictions
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Free to All
- Access Instructions
- The NCBI Gene Expression Omnibus and BioProject databases provide open access to these files.
- Associated Publications
- Equipment Used
- Dataset Format(s)
- TAR, TXT, BW
- Dataset Size
- 15.1 GB
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