Targeting the Oncogenic Long Non-coding RNA SLNCR1 by Blocking Its Sequence-Specific Binding to the Androgen Receptor

Long non-coding RNAs (lncRNAs) are critical regulators of numerous physiological processes and diseases, especially cancers. However, development of lncRNA-based therapies is limited because the mechanisms of many lncRNAs are obscure, and interactions with functional partners, including proteins, remain uncharacterized. The lncRNA SLNCR1 binds to and regulates the androgen receptor (AR) to mediate melanoma invasion and proliferation in an androgen-independent manner. Here, we use biochemical analyses coupled with selective 2′-hydroxyl acylation analyzed by primer extension (SHAPE) RNA structure probing to show that the N-terminal domain of AR binds a pyrimidine-rich motif in an unstructured region of SLNCR1. This motif is predictive of AR binding, as we identify an AR-binding motif in lncRNA HOXA11-AS-203. Oligonucleotides that bind either the AR N-terminal domain or the AR RNA motif block the SLNCR1-AR interaction and reduce SLNCR1-mediated melanoma invasion. Delivery of oligos that block SLNCR1-AR interaction thus represent a plausible therapeutic strategy. [Display omitted] •The N-terminal region of AR binds unstructured RNA in a sequence-specific manner•An unstructured lncRNA region scaffolds an invasion-promoting transcription complex•An identified AR RNA-binding motif is predictive of other lncRNA-AR interactions•Sterically blocking the SLNCR-AR interaction blocks melanoma invasion Androgen receptor (AR)-RNA complexes have been implicated in cancer, including melanoma. Schmidt et al. demonstrate that AR binds a single strand sequence in the long non-coding RNA (lncRNA) SLNCR. Point mutations or oligonucleotides that abrogate AR binding to SLNCR block melanoma invasion, suggesting that targeting lncRNA-protein complexes holds therapeutic promise.