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

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Small molecule drug discovery traditionally targets proteins, but RNA targets offer new therapeutic potential.
• Overexpression of the MALAT1 long non-coding RNA (lncRNA) is linked to poor patient survival in certain cancers.
• Targeting lncRNAs like MALAT1 could modulate disease-driving mechanisms.

Purpose of the Study:

• To identify small molecules that modulate the oncogenic MALAT1 lncRNA within a cellular context.
• To explore RNA as a druggable target space for cancer therapeutics.

Main Methods:

• A high-content imaging screen utilizing fluorescence in-situ hybridization was employed.
• A library of FDA-approved drugs and known bioactive molecules was screened.
• Mode-of-action studies were conducted to elucidate the regulatory pathway.

Main Results:

• Two compounds, including the FDA-approved drug Niclosamide, were identified that significantly decrease MALAT1 nuclear levels.
• Niclosamide demonstrated good potency in reducing MALAT1 levels.
• A novel pathway involving GSK3B activation and heterogeneous nuclear ribonucleoproteins (hnRNPs) was implicated in MALAT1 regulation.

Conclusions:

• Small molecules can effectively modulate oncogenic lncRNA levels, specifically MALAT1.
• Niclosamide and its mechanism represent a potential therapeutic strategy for cancers associated with MALAT1 overexpression.
• This study provides a foundation for developing novel cancer treatments targeting lncRNAs.