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Small molecule quercetin binds MALAT1 triplex and modulates its cellular function.

Isha Rakheja1,2, Asgar Hussain Ansari1,2, Arjun Ray3

  • 1Chemical and Systems Biology Unit, Council of Scientific and Industrial Research-Institute of Genomics & Integrative Biology, New Delhi 110025, India.

Molecular Therapy. Nucleic Acids
|October 26, 2022
PubMed
Summary
This summary is machine-generated.

Quercetin binds to the metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) triplex, downregulating its levels and modulating downstream genes. This suggests quercetin as a potential therapeutic scaffold for MALAT1-related cancers.

Keywords:
MALAT1MT: Oligonucleotides: Therapies and ApplicationsRNA FISHin silico dockingisothermal titration calorimetryquercetinsmall-molecule bindingtriple helix

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Area of Science:

  • Molecular Biology
  • RNA Biology
  • Pharmacology

Background:

  • Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a long non-coding RNA implicated in oncogenesis.
  • The 3' triple-helix structure of MALAT1 is a potential target for therapeutic intervention.
  • Quercetin is a known molecule capable of binding to RNA triplex structures.

Purpose of the Study:

  • To investigate the binding interaction between quercetin and the MALAT1 triplex.
  • To determine the functional consequences of quercetin binding on MALAT1 expression and activity.
  • To explore the potential of quercetin as a therapeutic agent or research tool for MALAT1-related diseases.

Main Methods:

  • UV-visible spectroscopy, circular dichroism spectroscopy, and isothermal titration calorimetry were used to characterize quercetin-MALAT1 triplex binding.
  • Real-time PCR and fluorescence in situ hybridization (FISH) were employed to assess MALAT1 transcript and localization changes.
  • Transcription-stop assays and transcriptome-wide analysis were performed to confirm direct interaction and identify downstream effects.

Main Results:

  • Quercetin demonstrated a strong binding affinity (Kd = 495 ± 61 nM) to the MALAT1 triplex with a 1:1 stoichiometry.
  • Quercetin induced approximately 50% downregulation of MALAT1 transcripts in MCF7 cells and reduced its presence in nuclear speckles.
  • Direct interaction was confirmed, and quercetin treatment led to modulation of MALAT1 downstream gene expression and alternative splicing.

Conclusions:

  • Quercetin effectively binds to the MALAT1 triplex, leading to significant functional modulation.
  • Quercetin's ability to downregulate MALAT1 suggests its potential as a therapeutic lead compound.
  • The study highlights quercetin as a valuable chemical tool for further research into MALAT1 functions and therapeutic development.