Targeting the Oncogenic Long Non-coding RNA SLNCR1 by Blocking Its Sequence-Specific Binding to the Androgen Receptor
Summary: 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 pro...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2020-01-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S221112471931650X |
| _version_ | 1818132190249091072 |
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| author | Karyn Schmidt Chase A. Weidmann Thomas A. Hilimire Elaine Yee Breanne M. Hatfield John S. Schneekloth, Jr. Kevin M. Weeks Carl D. Novina |
| author_facet | Karyn Schmidt Chase A. Weidmann Thomas A. Hilimire Elaine Yee Breanne M. Hatfield John S. Schneekloth, Jr. Kevin M. Weeks Carl D. Novina |
| author_sort | Karyn Schmidt |
| collection | DOAJ |
| description | Summary: 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. : 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. Keywords: long non-coding RNA, hormone receptor, androgen receptor, HOXA11AS, LINC00673, antisense oligos, melanoma, invasion, RNA scaffold, SHAPE |
| first_indexed | 2024-12-11T08:32:53Z |
| format | Article |
| id | doaj.art-9d6be757e5b14c61a203d93299ae6d6f |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-11T08:32:53Z |
| publishDate | 2020-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-9d6be757e5b14c61a203d93299ae6d6f2022-12-22T01:14:25ZengElsevierCell Reports2211-12472020-01-01302541554.e5Targeting the Oncogenic Long Non-coding RNA SLNCR1 by Blocking Its Sequence-Specific Binding to the Androgen ReceptorKaryn Schmidt0Chase A. Weidmann1Thomas A. Hilimire2Elaine Yee3Breanne M. Hatfield4John S. Schneekloth, Jr.5Kevin M. Weeks6Carl D. Novina7Department 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, USADepartment of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-3290, USAChemical Biology Laboratory, National Cancer Institute, Frederick, MD 21702, USADepartment 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, USADepartment of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-3290, USAChemical Biology Laboratory, National Cancer Institute, Frederick, MD 21702, USADepartment of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-3290, USADepartment 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; Corresponding authorSummary: 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. : 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. Keywords: long non-coding RNA, hormone receptor, androgen receptor, HOXA11AS, LINC00673, antisense oligos, melanoma, invasion, RNA scaffold, SHAPEhttp://www.sciencedirect.com/science/article/pii/S221112471931650X |
| spellingShingle | Karyn Schmidt Chase A. Weidmann Thomas A. Hilimire Elaine Yee Breanne M. Hatfield John S. Schneekloth, Jr. Kevin M. Weeks Carl D. Novina Targeting the Oncogenic Long Non-coding RNA SLNCR1 by Blocking Its Sequence-Specific Binding to the Androgen Receptor Cell Reports |
| title | Targeting the Oncogenic Long Non-coding RNA SLNCR1 by Blocking Its Sequence-Specific Binding to the Androgen Receptor |
| title_full | Targeting the Oncogenic Long Non-coding RNA SLNCR1 by Blocking Its Sequence-Specific Binding to the Androgen Receptor |
| title_fullStr | Targeting the Oncogenic Long Non-coding RNA SLNCR1 by Blocking Its Sequence-Specific Binding to the Androgen Receptor |
| title_full_unstemmed | Targeting the Oncogenic Long Non-coding RNA SLNCR1 by Blocking Its Sequence-Specific Binding to the Androgen Receptor |
| title_short | Targeting the Oncogenic Long Non-coding RNA SLNCR1 by Blocking Its Sequence-Specific Binding to the Androgen Receptor |
| title_sort | targeting the oncogenic long non coding rna slncr1 by blocking its sequence specific binding to the androgen receptor |
| url | http://www.sciencedirect.com/science/article/pii/S221112471931650X |
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