Sarcoma Medical Oncology Department, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
Nat Commun. 2022 Jun 1;13(1):3057. doi: 10.1038/s41467-022-30710-z.
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.
促结缔组织增生性小圆细胞肿瘤（DSRCT）是一种侵袭性的、通常无法治愈的肉瘤亚型，主要发生在青春期后的年轻男性中。最近的证据表明，雄激素受体（AR）可以促进 DSRCT 中的肿瘤进展。然而，AR 诱导的致癌刺激的机制仍未确定。在此，我们证明恩扎卢胺和 AR 定向反义寡核苷酸（AR-ASO）可阻断 5α-二氢睾酮（DHT）诱导的 DSRCT 细胞增殖，并降低异种移植肿瘤负担。进行了基因表达分析和染色质免疫沉淀测序（ChIP-seq），以阐明 AR 信号如何调节细胞表观遗传程序。值得注意的是，ChIP-seq 揭示了 AR 与关键致癌调节剂（包括 WT1（标志性融合蛋白的 C 末端伴侣）和 FOXF1）附近的新型 DSRCT 特异性 AR DNA 结合位点。此外，AR 占据了调节 Wnt 通路、神经分化和胚胎器官发育的增强子位点，表明 AR 参与了功能失调的细胞谱系决定。鉴于广泛使用 FDA 批准的用于前列腺癌的雄激素靶向药物，我们的发现具有直接的临床意义。
