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- Title
The androgen receptor is a therapeutic target in desmoplastic small round cell sarcoma.
- Authors
Lamhamedi-Cherradi, Salah-Eddine; Maitituoheti, Mayinuer; Menegaz, Brian A.; Krishnan, Sandhya; Vetter, Amelia M.; Camacho, Pamela; Wu, Chia-Chin; Beird, Hannah C.; Porter, Robert W.; Ingram, Davis R.; Ramamoorthy, Vandhana; Mohiuddin, Sana; McCall, David; Truong, Danh D.; Cuglievan, Branko; Futreal, P. Andrew; Velasco, Alejandra Ruiz; Anvar, Nazanin Esmaeili; Utama, Budi; Titus, Mark
- Abstract
Desmoplastic small round cell tumor (DSRCT) is an aggressive, usually incurable sarcoma subtype that predominantly occurs in post-pubertal young males. Recent evidence suggests that the androgen receptor (AR) can promote tumor progression in DSRCTs. However, the mechanism of AR-induced oncogenic stimulation remains undetermined. Herein, we demonstrate that enzalutamide and AR-directed antisense oligonucleotides (AR-ASO) block 5α-dihydrotestosterone (DHT)-induced DSRCT cell proliferation and reduce xenograft tumor burden. Gene expression analysis and chromatin immunoprecipitation sequencing (ChIP-seq) were performed to elucidate how AR signaling regulates cellular epigenetic programs. Remarkably, ChIP-seq revealed novel DSRCT-specific AR DNA binding sites adjacent to key oncogenic regulators, including WT1 (the C-terminal partner of the pathognomonic fusion protein) and FOXF1. Additionally, AR occupied enhancer sites that regulate the Wnt pathway, neural differentiation, and embryonic organ development, implicating AR in dysfunctional cell lineage commitment. Our findings have direct clinical implications given the widespread availability of FDA-approved androgen-targeted agents used for prostate cancer. Androgen receptor can promote tumour progression in desmoplastic small round cell tumour (DSRCT), an aggressive paediatric malignancy that predominantly affects young males. Here, the authors show that DSRCT is an AR-driven malignancy and sensitive to androgen deprivation therapy
- Subjects
UNITED States. Food &; Drug Administration; ANDROGEN receptors; ANDROGEN deprivation therapy; CHIMERIC proteins; SARCOMA; MORPHOGENESIS; BINDING sites
- Publication
Nature Communications, 2022, Vol 13, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-022-30710-z