High Throughput FISH Screening Identifies Small Molecules That Modulate Oncogenic lncRNA MALAT1 via GSK3B and hnRNPs

Zablowsky, Nina; Farack, Lydia; Rofall, Sven; Kramer, Jan; Meyer, Hanna; Nguyen, Duy; Ulrich, Alexander K. C.; Bader, Benjamin; Steigemann, Patrick

doi:10.3390/ncrna9010002

Open AccessArticle

High Throughput FISH Screening Identifies Small Molecules That Modulate Oncogenic lncRNA MALAT1 via GSK3B and hnRNPs

by

Nina Zablowsky

,

Lydia Farack

,

Sven Rofall

,

Jan Kramer

,

Hanna Meyer

,

Duy Nguyen

,

Alexander K. C. Ulrich

,

Benjamin Bader

and

Patrick Steigemann

^*

Nuvisan ICB GmbH, Müllerstrasse 178, 13156 Berlin, Germany

^*

Author to whom correspondence should be addressed.

Non-Coding RNA 2023, 9(1), 2; https://doi.org/10.3390/ncrna9010002

Submission received: 6 October 2022 / Revised: 12 December 2022 / Accepted: 20 December 2022 / Published: 3 January 2023

(This article belongs to the Section Long Non-Coding RNA)

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Abstract

Traditionally, small molecule-based drug discovery has mainly focused on proteins as the drug target. Opening RNA as an additional target space for small molecules offers the possibility to therapeutically modulate disease-driving non-coding RNA targets as well as mRNA of otherwise undruggable protein targets. MALAT1 is a highly conserved long-noncoding RNA whose overexpression correlates with poor overall patient survival in some cancers. We report here a fluorescence in-situ hybridization-based high-content imaging screen to identify small molecules that modulate the oncogenic lncRNA MALAT1 in a cellular setting. From a library of FDA approved drugs and known bioactive molecules, we identified two compounds, including Niclosamide, an FDA-approved drug, that lead to a rapid decrease of MALAT1 nuclear levels with good potency. Mode-of-action studies suggest a novel cellular regulatory pathway that impacts MALAT1 lncRNA nuclear levels by GSK3B activation and the involvement of the RNA modulating family of heterogenous nuclear ribonucleoproteins (hnRNPs). This study is the basis for the identification of novel targets that lead to a reduction of the oncogenic lncRNA MALAT1 in a cancer setting.

Keywords: FISH based high-content screening; novel MALAT1 destabilizer; involvement of GSK3B in MALAT1 regulation

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MDPI and ACS Style

Zablowsky, N.; Farack, L.; Rofall, S.; Kramer, J.; Meyer, H.; Nguyen, D.; Ulrich, A.K.C.; Bader, B.; Steigemann, P. High Throughput FISH Screening Identifies Small Molecules That Modulate Oncogenic lncRNA MALAT1 via GSK3B and hnRNPs. Non-Coding RNA 2023, 9, 2. https://doi.org/10.3390/ncrna9010002

AMA Style

Zablowsky N, Farack L, Rofall S, Kramer J, Meyer H, Nguyen D, Ulrich AKC, Bader B, Steigemann P. High Throughput FISH Screening Identifies Small Molecules That Modulate Oncogenic lncRNA MALAT1 via GSK3B and hnRNPs. Non-Coding RNA. 2023; 9(1):2. https://doi.org/10.3390/ncrna9010002

Chicago/Turabian Style

Zablowsky, Nina, Lydia Farack, Sven Rofall, Jan Kramer, Hanna Meyer, Duy Nguyen, Alexander K. C. Ulrich, Benjamin Bader, and Patrick Steigemann. 2023. "High Throughput FISH Screening Identifies Small Molecules That Modulate Oncogenic lncRNA MALAT1 via GSK3B and hnRNPs" Non-Coding RNA 9, no. 1: 2. https://doi.org/10.3390/ncrna9010002

APA Style

Zablowsky, N., Farack, L., Rofall, S., Kramer, J., Meyer, H., Nguyen, D., Ulrich, A. K. C., Bader, B., & Steigemann, P. (2023). High Throughput FISH Screening Identifies Small Molecules That Modulate Oncogenic lncRNA MALAT1 via GSK3B and hnRNPs. Non-Coding RNA, 9(1), 2. https://doi.org/10.3390/ncrna9010002

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High Throughput FISH Screening Identifies Small Molecules That Modulate Oncogenic lncRNA MALAT1 via GSK3B and hnRNPs

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