Abstract
SUMMARYMelanoma is the deadliest form of skin cancer, affecting men more frequently and severely than women. Although recent studies suggest that differences in activity of the androgen receptor (AR) underlie the observed sex bias, little is known about AR activity in melanoma. Here we show that AR and EGR1 bind to the long non-coding RNA SLNCR and increase melanoma proliferation through coordinated transcriptional regulation of several growth-regulatory genes. ChIP-seq reveals that ligand-free AR is enriched on SLNCR-regulated melanoma genes and that AR genomic occupancy significantly overlaps with EGR1 at consensus EGR1 binding sites. We present a model in which SLNCR recruits AR to EGR1-bound genomic loci and switches EGR1-mediated transcriptional activation to repression of the tumor suppressor p21Waf1/Cip1. Our data implicate the regulatory triad of SLNCR, AR, and EGR1 in promoting oncogenesis and may help explain why men have a higher incidence of and more rapidly progressive melanomas compared with women.
Highlights
The worldwide incidence of melanoma has been on the rise for the past 30 years
In addition to androgen receptor (AR) and Brn3a, both of which are required for SLNCR1-mediated regulation of MMP9, we identified early growth response 1 (EGR1) as a candidate SLNCR1-interacting transcription factor (Schmidt et al, 2016)
We demonstrated previously that SLNCR1 binds to AR and recruits it to the MMP9 promoter and that SLNCR1 and AR are required for transcriptionally upregulating MMP9 expression and promoting melanoma invasion (Schmidt et al, 2016)
Summary
The worldwide incidence of melanoma has been on the rise for the past 30 years. In the United States, there are $73,000 new cases diagnosed and $10,000 deaths annually attributed to melanoma (Siegel et al, 2015). In direct support of an oncogenic function for AR, we recently showed that AR increases melanoma invasion through transcriptional upregulation of the matrix metalloproteinase MMP9 (Schmidt et al, 2016). This regulation occurs independently of canonical AR activation, in which an androgen (such as testosterone) binds to the receptor to elicit downstream transcriptional patterns. AR-mediated invasion requires a novel lncRNA, SLNCR; the abundant SLNCR1 isoform that directly binds to and recruits AR to the MMP9 promoter
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