New Delhi: A group of researchers discovered a novel role for cancer-causing genes in controlling a key genetic process that underlies genetic variation in prostate cancer.
The research was led by the Barts Cancer Institute (BCI), the Italian Institute for Genomic Medicine and the University of Milan at Queen Mary University of London. The findings were published in the journal Cell Reports, revealing how the gene affects the generation of genetic variants in prostate cancer that may predict disease survival and represent new drug targets to improve patient survival. could.
Co-senior author Dr Prabhakar Rajan, Group Leader at BCI and Consultant Urological Surgeon at Barts Health NHS Trust, said: “Prostate cancer is the most common male cancer in the world and the leading cause of male cancer-related death. It is very variable. Its genetic architecture, which makes diagnosis and treatment difficult, because there is no one-size-fits-all approach to treating patients. Knowledge of the drivers of genetic variability may help us better understand the disease and improve treatments. will do.”
Alternative splicing is the process in which segments of genes are shuffled to form different combinations of genetic code known as ‘splice variants’, which provide instructions for making proteins. Through alternative splicing, a single gene can code for many different proteins that are expressed at different levels and perform different functions in the cell.
Alternative splicing is an important process for regulating gene expression and generating genetic and protein diversity within normal cells; However, it is inhibited in several types of cancer, including prostate cancer.
In this study, the team identified that the cancer-causing gene FOXA1 is a key regulator of alternative splicing in prostate cancer and may control the generation of splice variants that affect disease relapse and patient survival.
FOXA1 corrects alternative splicing in prostate cancer
FOXA1 is a type of protein known as a leading transcription factor. Transcription factors can choose which genes in the DNA carry the instructions used to make proteins within our cells and the rate at which this occurs. As a leading factor, FOXA1 opens DNA for binding by different transcription factors. Alterations in FOXA1 have been found to promote the initiation and progression of prostate cancer.
By assessing alternative splicing in cell line models and primary cases of prostate cancer, the team found that high levels of FOXA1 limit genetic diversity toward splice variants that have a functional advantage for cancer cells. Investigations revealed that FOXA1 preferred splice variants that were present at high levels within cells and silent splice variants expressed at low levels, thus reducing splicing variability in prostate cancer.
Dr Rajan said: “This unique finding has never been shown before for a controller of alternative splicing and may mean that FOXA1 directs prostate cancer cells to function in a specific way that is important for patients. could be harmful.”
Co-senior author Professor Matteo Cereda, Associate Professor at the University of Milan and Group Leader at the Italian Institute for Genomic Medicine, said: “For the first time we show that an early player of transcription regulation is also responsible for fine-tuning alternative addition.”
Potential new targets for treatment
To determine whether FOXA1-controlled alternative splicing had an effect on patient survival, the team analyzed clinical data from more than 300 patients with primary prostate cancer, available through the Cancer Genome Atlas.
Although high levels of FOXA1 reduced splicing variability, the team found that FOXA1 encodes genetic segments involved in splice variants that are strong markers of prostate cancer recurrence. Using prostate cancer cell lines, the team revealed that the inclusion of a particular genetic segment in the splice version of a gene called the FLNA gene, which is regulated by FOXA1, confers a growth advantage to prostate cancer cells, Which can get rid of the initial disease.
Dr. Rajan said: “This study shows how we can exploit the power of genomics to make important scientific discoveries about how genetic variability is controlled in prostate cancer. We hope that our findings will be useful.” It will have clinical implications by identifying more accurate markers of disease recurrence and potential for new drug targets.”
The team would now like to test further whether the splice variants they have identified to be associated with cancer recurrence are actually useful in predicting disease relapse, and to conduct experiments to determine whether Whether targeting these genes could represent new ways of treating prostate cancer remains to be seen.