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

  1. Author:
    Schmidt, Karyn
    Weidmann, Chase A
    Hilimire, Thomas A
    Yee, Elaine
    Hatfield, Breanne M
    Schneekloth,Jay
    Weeks, Kevin M
    Novina, Carl D

  2. Author Address

    Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02141, USA., Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-3290, USA., Chemical Biology Laboratory, National Cancer Institute, Frederick, MD 21702, USA., Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02141, USA. Electronic address: carl_novina@dfci.harvard.edu.,
    1. Year: 2020
    2. Date: Jan 14
  2. Journal: Cell reports
    1. 30
    2. 2
    3. Pages: 541-554.e5
  4. Type of Article: Article
  5. ISSN: 2211-1247
  1. Abstract:

    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. Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.

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External Sources

  1. View Full Text
  2. DOI: 10.1016/j.celrep.2019.12.011
  3. PMID: 31940495
  4. View record in Web of Science®
  5. WOS: 000507498100019
  6. PII : S2211-1247(19)31650-X

Library Notes

  1. Fiscal Year: FY2019-2020
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