TY - JOUR
T1 - The androgen receptor is a therapeutic target in desmoplastic small round cell sarcoma
AU - Lamhamedi-Cherradi, Salah-Eddine
AU - Maitituoheti, Mayinuer
AU - Menegaz, Brian A
AU - Krishnan, Sandhya
AU - Vetter, Amelia M
AU - Camacho, Pamela
AU - Wu, Chia-Chin
AU - Beird, Hannah C
AU - Porter, Robert W
AU - Ingram, Davis R
AU - Ramamoorthy, Vandhana
AU - Mohiuddin, Sana
AU - McCall, David
AU - Truong, Danh D
AU - Cuglievan, Branko
AU - Futreal, P Andrew
AU - Velasco, Alejandra Ruiz
AU - Anvar, Nazanin Esmaeili
AU - Utama, Budi
AU - Titus, Mark
AU - Lazar, Alexander J
AU - Wang, Wei-Lien
AU - Rodriguez-Aguayo, Cristian
AU - Ratan, Ravin
AU - Livingston, J Andrew
AU - Rai, Kunal
AU - MacLeod, A Robert
AU - Daw, Najat C
AU - Hayes-Jordan, Andrea
AU - Ludwig, Joseph A
N1 - © 2022. The Author(s).
PY - 2022/6/1
Y1 - 2022/6/1
N2 - 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.
AB - 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.
KW - Androgen Receptor Antagonists/pharmacology
KW - Androgens
KW - Animals
KW - Cell Line, Tumor
KW - Desmoplastic Small Round Cell Tumor/genetics
KW - Humans
KW - Male
KW - Oligonucleotides, Antisense/pharmacology
KW - Receptors, Androgen/genetics
KW - Xenograft Model Antitumor Assays
U2 - 10.1038/s41467-022-30710-z
DO - 10.1038/s41467-022-30710-z
M3 - Article
C2 - 35650195
SN - 2041-1723
VL - 13
SP - 3057
JO - Nature communications
JF - Nature communications
IS - 1
ER -