Faculty, Staff and Student Publications
Publication Date
2-7-2024
Journal
Nature Communications
Abstract
The t(X,17) chromosomal translocation, generating the ASPSCR1::TFE3 fusion oncoprotein, is the singular genetic driver of alveolar soft part sarcoma (ASPS) and some Xp11-rearranged renal cell carcinomas (RCCs), frustrating efforts to identify therapeutic targets for these rare cancers. Here, proteomic analysis identifies VCP/p97, an AAA+ ATPase with known segregase function, as strongly enriched in co-immunoprecipitated nuclear complexes with ASPSCR1::TFE3. We demonstrate that VCP is a likely obligate co-factor of ASPSCR1::TFE3, one of the only such fusion oncoprotein co-factors identified in cancer biology. Specifically, VCP co-distributes with ASPSCR1::TFE3 across chromatin in association with enhancers genome-wide. VCP presence, its hexameric assembly, and its enzymatic function orchestrate the oncogenic transcriptional signature of ASPSCR1::TFE3, by facilitating assembly of higher-order chromatin conformation structures demonstrated by HiChIP. Finally, ASPSCR1::TFE3 and VCP demonstrate co-dependence for cancer cell proliferation and tumorigenesis in vitro and in ASPS and RCC mouse models, underscoring VCP's potential as a novel therapeutic target.
Keywords
Animals, Mice, Humans, Proteomics, Carcinoma, Renal Cell, Translocation, Genetic, Oncogene Proteins, Fusion, Kidney Neoplasms, Chromatin, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Chromosomes, Human, X, Intracellular Signaling Peptides and Proteins, Valosin Containing Protein
DOI
10.1038/s41467-024-45280-5
PMID
38326311
PMCID
PMC10850509
PubMedCentral® Posted Date
2-7-2024
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Included in
Bioinformatics Commons, Biomedical Informatics Commons, Genetic Phenomena Commons, Medical Genetics Commons, Oncology Commons