Researchers from the Barts Cancer Institute (BCI) at Queen Mary University of London, the Italian Institute for Genomic Medicine, and the University of Milan have identified a new role for a cancer-causing gene in controlling an important genetic process that underpins genetic variation in the prostate. cancer.
Results published today in cell reportsreveals how the gene influences the generation of genetic variants in prostate cancer that may predict disease relapse and represent novel drug targets to improve patient survival.
Prostate cancer is the most common male cancer in the world and the leading cause of death related to male cancer. It is very variable in its genetic makeup, which makes diagnosis and treatment difficult, as there is no one-size-fits-all approach to treating patients. Knowledge of the drivers of genetic variation will help us better understand the disease and improve treatments.”
Dr Prabhakar Rajan, co-first author and group leader at BCI and Consultant Urologist at Barts Health NHS Trust
Alternative splicing is the process by which parts of genes are shuffled to create different sets of genetic code known as “splice variants,” which provide the instructions needed to make proteins. Through alternative splicing, a single gene can code for many different proteins that are expressed at different levels and have different functions in the cell.
Alternative splicing is an important process for the regulation of gene expression and the generation of genetic and protein diversity within normal cells; However, it is inactivated in many types of cancer, including prostate cancer.
In this study, the team identified that the oncogenic gene FOXA1 is a master regulator of alternative splicing in prostate cancer and may control the generation of splice variants that affect disease relapse and patient survival.
FOXA1 modulates alternative splicing in prostate cancer
FOXA1 is a type of protein known as a leading transcription factor. Transcription factors can determine which genes in our DNA are transcribed in the instructions used to make proteins within our cells, and how often. As a leading factor, FOXA1 opens DNA for binding by distinct transcription factors. Changes in FOXA1 have been found to drive the initiation and progression of prostate cancer.
By evaluating alternative splicing in cell-line models and primary cases of prostate cancer, the team found that high levels of FOXA1 limited genetic diversity toward splice variants that have a functional benefit to cancer cells. Investigations revealed that FOXA1 preferred splice variants that were present at high intracellular levels and silenced splice variants expressed at low levels, thus reducing splice variation in prostate cancer.
“This unique finding has never before been shown for an alternative splicing controller and may mean that FOXA1 directs prostate cancer cells to act in a certain way that may be harmful to patients,” said Dr. Rajan.
Co-senior author Professor Matteo Cerida, associate professor at the University of Milan and group leader at the Italian Institute of Genomic Medicine, added: “For the first time we show that an early player in transcriptional regulation is also responsible for fine-tuning alternative splicing.”
Potential new targets for treatment
To determine whether FOXA1-controlled variant splicing has an impact on patient survival, the team analyzed clinical data from more than 300 primary prostate cancer patients, available via The Cancer Genome Atlas.
Although high levels of FOXA1 reduced splice diversity, the team found that FOXA1 promoted the inclusion of gene segments in splice variants that are strong markers of prostate cancer recurrence. Using prostate cancer cell lines, the team revealed that inserting a specific gene segment into a splice variant of a gene called FLNA The gene, controlled by FOXA1, confers a growth advantage on prostate cancer cells, which may lead to early disease relapse.
Dr. Rajan said: “This study demonstrates how we can harness the power of genomics to make important scientific discoveries about how genetic variation in prostate cancer is controlled. We hope that our findings will have a clinical impact by identifying more precise markers of disease recurrence and new potential drug targets.”
The team now would like to further test whether the splice variants they identified are associated with cancer recurrence is useful in actually predicting disease relapse, and to conduct experiments to determine whether targeting these genes could represent new avenues for treating prostate cancer.
Dr Rajan’s work on this study was supported by funding from Cancer Research UK, Barts Charity, Orchid Charity, Royal College of Surgeons of England and Urology Foundation.
Professor Cereda’s work in this study was supported by funding from AIRC, the Fondazione Compagnia di San Paolo, and the Fondazione Piemontese per la Ricerca sul Cancro Onlus through the Fondazione del Piemonte per l’Oncologia.