Selective Control of Tumor Gene Expression... "Personalized Cancer Therapy Expected"

The mechanism behind the expression of the tumor gene 'BCL3' has been identified, raising expectations that this will have a positive impact on the development of personalized cancer treatment strategies. BCL3 acts as a kind of switch, being overexpressed in cancers such as breast and colorectal cancer, thereby promoting the growth, survival, and metastasis of cancer cells.

On September 5, the National Research Foundation of Korea announced that the research team led by Professor Kyungkyu Kim at Sungkyunkwan University had identified the regulatory mechanism by which the 'guanine quadruplex (G4)' knot structure in DNA and ribonucleic acid (RNA) either promotes or suppresses the expression of BCL3.

Schematic diagram of the regulatory mechanism of tumor gene BCL3 expression through guanine quadruplex knot. Provided by Professor Kyungkyu Kim, Sungkyunkwan University

The G4 structure refers to a DNA quadruple helix structure formed in regions where guanine (G), one of the DNA bases, is repeated. While the original structure of DNA is a double helix, the research team explained that G4 structures have been found in specific regions and that these structures can be involved in various biological functions, such as gene expression regulation.

Recently, approaches targeting biological switches have attracted attention as new strategies for developing anticancer drugs that complement existing chemical and immunotherapies. This is because biological switches play a precise role in regulating the expression of tumor genes.

The expression of tumor genes is known to be regulated by the DNA sequence of gene promoters (base sequences that determine when, where, and how much a gene is expressed), transcription factors (proteins that read genetic information from DNA and combine with RNA polymerase to control transcription), and transcriptional condensates, which are protein-nucleic acid complexes.

Transcriptional condensates are liquid-state protein-RNA complexes that form spontaneously during the process of 'liquid-liquid phase separation' in the regions of the cell nucleus where gene transcription occurs. They gather at specific sites to regulate gene expression.

However, until now, only a few reports have indicated that DNA G4 knot structures bind to transcription factors, contribute to the formation of transcriptional condensates, and regulate tumor gene expression, while the regulatory mechanism involving RNA G4 has not yet been elucidated. This highlights the significance of the research team's discovery of the mechanism regulating BCL3 expression.

In this study, the research team confirmed that the G4 knots in DNA and RNA act as switches that respectively promote (ON) and suppress (OFF) the formation of transcriptional condensates essential for BCL3 expression.

The DNA G4 knot acts as a promoting switch by binding to the transcription factor SP1 (a protein that binds to the gene promoter and promotes gene transcription), thereby forming transcriptional condensates and enhancing BCL3 expression. In contrast, the RNA G4 knot acts as a suppressing switch by pulling SP1 out of the transcriptional condensate and dismantling the condensate, thereby inducing transcriptional suppression.

The research team conducted drug experiments targeting the DNA and RNA G4 knots, confirming that BCL3 expression either increased or decreased, and thus demonstrated that tumor gene expression can be selectively regulated.

This is expected to serve as a milestone for 'personalized cancer treatment strategies' that precisely control tumor gene expression by targeting patient-specific DNA and RNA G4 knots.

Professor Kim stated, "This study is significant in that it presents a 'novel anticancer strategy' that selectively inhibits tumor gene expression by regulating the formation of transcriptional condensates mediated by DNA and RNA G4 knots." He added, "The research team plans to conduct follow-up studies to verify whether the same mechanism can be applied not only to BCL3 but also to other tumor genes, as well as to inflammatory and neurological diseases."

Meanwhile, this research was supported by the Mid-Career Research Program funded by the Ministry of Science and ICT and the National Research Foundation of Korea. The results were also published in the international journal 'Nucleic Acids Research' on August 30.

This content was produced with the assistance of AI translation services.