The therapeutically actionable long non-coding RNA 'T-RECS' is essential to cancer cells' survival in NRAS/MAPK-driven melanoma.

Antisense oligonucleotides Apoptosis HT-KAM MAPK-pathway Melanoma T-RECS hnRNPA2/B1 lncRNA

Journal

Molecular cancer
ISSN: 1476-4598
Titre abrégé: Mol Cancer
Pays: England
ID NLM: 101147698

Informations de publication

Date de publication:
22 Feb 2024
Historique:
received: 02 01 2024
accepted: 05 02 2024
medline: 22 2 2024
pubmed: 22 2 2024
entrez: 21 2 2024
Statut: epublish

Résumé

Finding effective therapeutic targets to treat NRAS-mutated melanoma remains a challenge. Long non-coding RNAs (lncRNAs) recently emerged as essential regulators of tumorigenesis. Using a discovery approach combining experimental models and unbiased computational analysis complemented by validation in patient biospecimens, we identified a nuclear-enriched lncRNA (AC004540.4) that is upregulated in NRAS/MAPK-dependent melanoma, and that we named T-RECS. Considering potential innovative treatment strategies, we designed antisense oligonucleotides (ASOs) to target T-RECS. T-RECS ASOs reduced the growth of melanoma cells and induced apoptotic cell death, while having minimal impact on normal primary melanocytes. Mechanistically, treatment with T-RECS ASOs downregulated the activity of pro-survival kinases and reduced the protein stability of hnRNPA2/B1, a pro-oncogenic regulator of MAPK signaling. Using patient- and cell line- derived tumor xenograft mouse models, we demonstrated that systemic treatment with T-RECS ASOs significantly suppressed the growth of melanoma tumors, with no noticeable toxicity. ASO-mediated T-RECS inhibition represents a promising RNA-targeting approach to improve the outcome of MAPK pathway-activated melanoma.

Identifiants

DOI: 10.1186/s12943-024-01955-7 PMID: 38383439
pubmed: 38383439
doi: 10.1186/s12943-024-01955-7
pii: 10.1186/s12943-024-01955-7
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

40

Subventions

Organisme : HDFCCC Laboratory for Cell Analysis Shared Resource Facility
ID : P30CA082103
Organisme : HDFCCC Laboratory for Cell Analysis Shared Resource Facility
ID : P30CA082103

Informations de copyright

© 2024. The Author(s).

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Auteurs

Valentin Feichtenschlager (V)

Department of Dermatology, Mt Zion Cancer Research Center, University of California San Francisco, 2340 Sutter Street, Room N461, San Francisco, CA, 94115, USA. valentin.feichtenschlager@hotmail.com.
Department of Dermatology, Academic Teaching Hospital, Clinic Landstrasse Vienna, Medical University Vienna, Vienna, Austria. valentin.feichtenschlager@hotmail.com.

Linan Chen (L)

Department of Dermatology, Mt Zion Cancer Research Center, University of California San Francisco, 2340 Sutter Street, Room N461, San Francisco, CA, 94115, USA.

Yixuan James Zheng (YJ)

Department of Dermatology, Mt Zion Cancer Research Center, University of California San Francisco, 2340 Sutter Street, Room N461, San Francisco, CA, 94115, USA.
School of Medicine, University of California San Francisco, San Francisco, CA, USA.

Wilson Ho (W)

Department of Dermatology, Mt Zion Cancer Research Center, University of California San Francisco, 2340 Sutter Street, Room N461, San Francisco, CA, 94115, USA.

Martina Sanlorenzo (M)

Department of Dermatology, Mt Zion Cancer Research Center, University of California San Francisco, 2340 Sutter Street, Room N461, San Francisco, CA, 94115, USA.

Igor Vujic (I)

Department of Dermatology, Mt Zion Cancer Research Center, University of California San Francisco, 2340 Sutter Street, Room N461, San Francisco, CA, 94115, USA.
Department of Dermatology, Academic Teaching Hospital, Clinic Landstrasse Vienna, Medical University Vienna, Vienna, Austria.
Faculty of Medicine, Sigmund Freud Private University, Vienna, Austria.

Eleanor Fewings (E)

Department of Dermatology, Mt Zion Cancer Research Center, University of California San Francisco, 2340 Sutter Street, Room N461, San Francisco, CA, 94115, USA.

Albert Lee (A)

Department of Dermatology, Mt Zion Cancer Research Center, University of California San Francisco, 2340 Sutter Street, Room N461, San Francisco, CA, 94115, USA.

Christopher Chen (C)

Department of Dermatology, Mt Zion Cancer Research Center, University of California San Francisco, 2340 Sutter Street, Room N461, San Francisco, CA, 94115, USA.

Ciara Callanan (C)

Department of Dermatology, Mt Zion Cancer Research Center, University of California San Francisco, 2340 Sutter Street, Room N461, San Francisco, CA, 94115, USA.

Kevin Lin (K)

Department of Dermatology, Mt Zion Cancer Research Center, University of California San Francisco, 2340 Sutter Street, Room N461, San Francisco, CA, 94115, USA.

Tiange Qu (T)

Department of Orofacial Science, Health Science West, University of California San Francisco School of Dentistry, San Francisco, CA, USA.

Dasha Hohlova (D)

Department of Dermatology, Mt Zion Cancer Research Center, University of California San Francisco, 2340 Sutter Street, Room N461, San Francisco, CA, 94115, USA.
Department of Biology, University of San Francisco, San Francisco, CA, USA.

Marin Vujic (M)

Department of Dermatology, Mt Zion Cancer Research Center, University of California San Francisco, 2340 Sutter Street, Room N461, San Francisco, CA, 94115, USA.
Department of Dermatology, Academic Teaching Hospital, Clinic Landstrasse Vienna, Medical University Vienna, Vienna, Austria.

Yeonjoo Hwang (Y)

Department of Hematology-Oncology, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.

Kevin Lai (K)

Department of Dermatology, Mt Zion Cancer Research Center, University of California San Francisco, 2340 Sutter Street, Room N461, San Francisco, CA, 94115, USA.

Stephanie Chen (S)

Department of Dermatology, Mt Zion Cancer Research Center, University of California San Francisco, 2340 Sutter Street, Room N461, San Francisco, CA, 94115, USA.

Thuan Nguyen (T)

Department of Dermatology, Mt Zion Cancer Research Center, University of California San Francisco, 2340 Sutter Street, Room N461, San Francisco, CA, 94115, USA.

Denise P Muñoz (DP)

Department of Hematology-Oncology, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.

Yoshinori Kohwi (Y)

Department of Orofacial Science, Health Science West, University of California San Francisco School of Dentistry, San Francisco, CA, USA.

Christian Posch (C)

Department of Dermatology, Mt Zion Cancer Research Center, University of California San Francisco, 2340 Sutter Street, Room N461, San Francisco, CA, 94115, USA.
Department of Dermatology, Academic Teaching Hospital, Clinic Landstrasse Vienna, Medical University Vienna, Vienna, Austria.
Faculty of Medicine, Sigmund Freud Private University, Vienna, Austria.
Department of Dermatology and Allergy, School of Medicine, German Cancer Consortium (DKTK), Technical University of Munich, Munich, Germany.

Adil Daud (A)

Department of Dermatology, Mt Zion Cancer Research Center, University of California San Francisco, 2340 Sutter Street, Room N461, San Francisco, CA, 94115, USA.

Klemens Rappersberger (K)

Department of Dermatology, Academic Teaching Hospital, Clinic Landstrasse Vienna, Medical University Vienna, Vienna, Austria.

Terumi Kohwi-Shigematsu (T)

Department of Orofacial Science, Health Science West, University of California San Francisco School of Dentistry, San Francisco, CA, USA.

Jean-Philippe Coppé (JP)

Department of Radiation Oncology, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.

Susana Ortiz-Urda (S)

Department of Dermatology, Mt Zion Cancer Research Center, University of California San Francisco, 2340 Sutter Street, Room N461, San Francisco, CA, 94115, USA.

Classifications MeSH