Article ; Online: Targeting the Oncogenic Long Non-coding RNA SLNCR1 by Blocking Its Sequence-Specific Binding to the Androgen Receptor.
2020 Volume 30, Issue 2, Page(s) 541–554.e5
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 ... ...
| 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. |
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| MeSH term(s) | Base Sequence ; Cell Line, Tumor ; Cell Proliferation/physiology ; Female ; HEK293 Cells ; Humans ; Male ; Melanoma/genetics ; Melanoma/metabolism ; Melanoma/pathology ; Neoplasm Invasiveness ; Protein Domains ; RNA, Long Noncoding/genetics ; RNA, Long Noncoding/metabolism ; RNA, Neoplasm/genetics ; RNA, Neoplasm/metabolism ; Receptors, Androgen/genetics ; Receptors, Androgen/metabolism |
| Chemical Substances | AR protein, human ; RNA, Long Noncoding ; RNA, Neoplasm ; Receptors, Androgen ; long non-coding RNA SLNCR1, human |
| Language | English |
| Publishing date | 2020-01-15 |
| Publishing country | United States |
| Document type | Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural |
| ZDB-ID | 2649101-1 |
| ISSN | 2211-1247 ; 2211-1247 |
| ISSN (online) | 2211-1247 |
| ISSN | 2211-1247 |
| DOI | 10.1016/j.celrep.2019.12.011 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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