G-quadruplexes in cancer-related gene promoters: from identification to therapeutic targeting

ABSTRACT

Introduction

Guanine-rich DNA sequences can fold into four-stranded noncanonical secondary structures called G-quadruplexes (G4s) which are widely distributed in functional regions of the human genome, such as telomeres and gene promoter regions. Compelling evidence suggests their involvement in key genome functions such as gene expression and genome stability. Notably, the abundance of G4-forming sequences near transcription start sites suggests their potential involvement in regulating oncogenes.

Areas covered

This review provides an overview of current knowledge on G4s in human oncogene promoters. The most representative G4-binding ligands have also been documented. The objective of this work is to present a comprehensive overview of the most promising targets for the development of novel and highly specific anticancer drugs capable of selectively impacting the expression of individual or a limited number of genes.

Expert opinion

Modulation of G4 formation by specific ligands has been proposed as a powerful new tool to treat cancer through the control of oncogene expression. Actually, most of G4-binding small molecules seem to simultaneously target a range of gene promoter G4s, potentially influencing several critical driver genes in cancer, thus producing significant therapeutic benefits.

KEYWORDS:

• Cancer
• DNA G-quadruplex
• G-quadruplex binding proteins
• G-quadruplex ligands
• G-quadruplex structures
• gene promoters
• oncogenes
• patents

Article highlights

• G-quadruplexes are widely distributed in functional regions of the human genome, such as telomeres and gene promoters.

• Evidence suggests G-quadruplex involvement in the regulation of oncogene expression establishing significant connections to cancer biology.

• The role of DNA G-quadruplexes in cellular processes make these structures promising targets for therapeutic intervention in cancer.

• This review provides an update of current knowledge on G-quadruplexes in human oncogene promoters together with their binding ligands, specifically designed to modulate gene expression.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by the Italian Association for Cancer Research (IG 26313 to A.R. and IG 24590 to B.P.).