Lnc’ing Non-coding RNAs to Melanoma Biology
Carl Novina, Assistant Professor, Dana Farber Cancer Institute
Long non-coding RNAs (lncRNAs) are critical regulators of numerous physiological processes and diseases, especially cancers. The tissue- and disease-specific expression of lncRNAs, as well as their gene-regulatory functions, makes lncRNAs ideal therapeutic targets. However, development of lncRNA-based cancer therapies is limited because the mechanisms of many lncRNAs are obscure. We identified a novel lncRNA, SLNCR, whose expression is associated with worse overall melanoma survival. SLNCR contains a highly-conserved sequence that binds to the androgen receptor (AR) and mediates increased melanoma invasion and proliferation in an androgen-independent manner. Thorough biochemical characterization of the AR-RNA interaction reveals that the N-terminal regulatory domain of AR binds to single-stranded RNA in a sequence-specific manner. To develop candidate therapeutics inhibiting the SLNCR- and AR-mediated invasion and proliferation, we designed 21-28 nucleotide oligos that are the (i) reverse complement to SLNCR’s AR binding sequence, which bind to SLNCR to generate double stranded RNA incapable of AR binding; or (ii) mimics of the SLNCR AR binding sequence, which bind directly to AR to preclude SLNCR binding. Both SLNCR- and AR-binding oligos are capable of sterically blocking the AR-SLNCR association. Delivery of these oligos to patient-derived melanoma cells reduces melanoma invasion and proliferation. Thus, these SLNCR- and AR-binding oligos represent novel therapeutic approaches for inhibition of melanoma growth and metastasis.
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