NEW YORK (GenomeWeb) – Researchers have uncovered a long non-coding RNA that is associated with androgen receptor signaling in prostate cancer progression and might serve as a drug target.
Prostate cancer, which affects nearly 165,000 men a year in the US, is typically hormone dependent and relies on androgen receptor signaling. Current therapies target the androgen receptor to halt the spread of the disease, but most patients become resistant to the treatment.
A University of Michigan-led team of researchers took a transcriptome analysis approach to uncover lncRNAs that might have a role in prostate cancer. As they reported yesterday in Nature Genetics, they homed in on ARLNC1, which is elevated in the disease and has a role in androgen receptor signaling. Through further functional analyses, they found ARLNC1 forms a positive feedback loop with the androgen receptor and could represent a treatment target.
"This study identifies a feedback loop that we could potentially disrupt as an alternative to blocking the androgen receptor directly," senior author Arul Chinnaiyan, director of the Michigan Center for Translational Pathology, said in a statement.
To find androgen receptor-regulated genes, he and his colleagues performed RNA sequencing on two androgen receptor-dependent prostate cancer cell lines, VCaP and LNCaP. They found 1,702 genes — including more than 500 lncRNAs — that were either induced or repressed in those cells. With androgen receptor chromatin immunoprecipitation sequencing data, they separated that list in two, one of genes directly regulated by the androgen receptor and the other of genes regulated indirectly. The directly regulated genes included 341 lncRNAs.
With samples from the Cancer Genome Atlas and the Stand Up to Cancer-Prostate Cancer Foundation, the researchers confirmed the expression of the androgen receptor-regulated genes in human prostate tissues.
One of the most differentially expressed genes among localized and metastatic prostate cancer was ARLNC1, the researchers reported. Within the TCGA cohort, they noted that ARLNC1 expression was highly specific to prostate cancer. Its expression was also specific to the prostate among normal tissue samples from the Genotype-Tissue Expression project, though the researchers noted that expression was significantly higher in cancerous than benign tissue.
In a series of functional assays, Chinnaiyan and his colleagues found that ARLNC1 transcription is directly regulated by the androgen receptor, as well as modestly by FOXA1. Loss of the androgen receptor or FOXA1 led to decreased ARLNC1 transcription. This, they added, accounts in part for the tissue specificity of ARLNC1, as androgen receptor and FOXA1 expression overlaps in the prostate.
They further found that knocking down ARLNC1 leads to the suppression of genes that are positively regulated by the androgen receptor and to the upregulation of genes negatively regulated by it. They also noted that ARLNC1 and AR transcripts co-localize to the nucleus, and that knocking down ARLNC1 led to an increase in the nuclear fraction of the androgen receptor, indicating that ARLNC1 regulates its cytoplasmic levels.
They form, the researchers added, a positive feedback loop in prostate cancer cell lines that keeps the androgen transcriptional program active.
This suggested to the team that targeting ARLNC1 could slow prostate cancer growth. Indeed, in a mouse xenograft model, they observed decreases in tumor growth in mice treated with an antisense oligonucleotide targeting ARLNC1.
"We're envisioning a potential therapy against ARLNC1 in combination with therapy to block the androgen receptor — which would hit the target and also this positive feedback loop," Chinnaiyan said.