The histone deacetylase inhibitor Scriptaid targets G-quadruplexes

Area of Science:

• Biochemistry
• Molecular Biology
• Cancer Research

Background:

• Scriptaid is a known histone deacetylase inhibitor with anti-tumoural properties.
• Its potential interaction with G-quadruplexes (G4s), despite structural similarities to known G4 ligands, remained unexplored.

Purpose of the Study:

• To investigate the cytotoxic activity and biological effects of Scriptaid in colorectal cancer (CRC) models.
• To identify and characterize the G-quadruplex (G4) targets of Scriptaid.

Main Methods:

• Synthesis of Scriptaid and screening of its cytotoxic activity in CRC cell lines.
• Evaluation of biological activity using cell cycle analysis, immunofluorescence, qRT-PCR, and Western blot.
• Identification of G4 targets through various binding assays.

Main Results:

• Scriptaid demonstrated significant cytotoxicity, induced cell cycle arrest, and caused nucleolar stress in CRC cells.
• The compound impaired RNA polymerase I (Pol I) transcription, stabilized G4 structures, and led to DNA damage.
• Binding assays confirmed Scriptaid interacts with G4s located in ribosomal DNA.

Conclusions:

• Scriptaid's anti-cancer effects in CRC are mediated by its interaction with G-quadruplexes (G4s) in ribosomal DNA.
• This interaction disrupts crucial cellular processes including transcription and DNA integrity.
• The study reveals G4 binding as a primary mechanism of action for Scriptaid in human cells.