Researchers at the Barts Cancer Institute at the Queen Mary University of London, the Italian Institute for Genomic Medicine, and the University of Milan may have identified a novel role for a cancer-causing gene in controlling an important genetic process that underpins genetic variation in prostate cancer, according to a new study published by Giudice et al in Cell Reports.
The findings reveal how the gene influences the generation of genetic variants in prostate cancer, which may predict disease relapse and represent new drug targets to improve patient survival.
“Prostate cancer is the [most common] male cancer in the world and [the leading] cause of male cancer–related death. It is very variable in its genetic makeup, which makes diagnosis and treatment tricky, as there is not a one-size-fits-all approach for treating patients. A knowledge of the drivers of genetic variability will help us understand the disease better, and improve treatments,” said co–senior author Prabhakar Rajan, PhD, FRCS, FHEA, a Group Leader at the Barts Cancer Institute and a consultant urologic surgeon at the Barts Health National Health Services Trust.
Research Methods and Findings
In this study, researchers 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 influence disease relapse and patient survival. Alternative splicing is an important process for regulating gene expression and generating genetic and protein diversity within normal cells; however, it is disrupted in many cancer types, including in prostate cancer.
FOXA1 is a pioneer transcription factor protein. As a pioneer factor, FOXA1 opens up DNA for binding by distinct transcription factors. Changes to FOXA1 have been found to drive the initiation and progression of prostate cancer.
By assessing alternative splicing in cell line models and primary cases of prostate cancer, researchers found that high levels of FOXA1 limited genetic diversity toward splice variants that have a functional benefit for the cancer cells. The investigations revealed that FOXA1 favored splice variants that were present at high levels within the cells and silenced splice variants expressed at low levels, consequently reducing the splicing variability in prostate cancer.
“This unique finding has never been shown before for a controller of alternative splicing and may mean that FOXA1 directs prostate cancer cells to act in a particular way that may be detrimental to patients,” said Dr. Rajan.
“For the first time, we showed that an early player of transcription regulation is also responsible for the fine-tuning of alternative splicing,” added co–senior study author Matteo Cereda, PhD, Associate Professor of Molecular Biology at the University of Milan and Group Leader at the Italian Institute for Genomic Medicine.
Potential New Targets for Treatment
To determine whether FOXA1-controlled alternative splicing had an impact on patient survival, researchers analyzed clinical data from The Cancer Genome Atlas Program for over 300 patients with primary prostate cancer.
Although high levels of FOXA1 reduced splicing variability, researchers found that the protein enhanced the inclusion of genetic segments into splice variants that were strong markers of prostate cancer recurrence. Using prostate cancer cell lines, researchers discovered that the inclusion of one particular genetic segment in the splice variant of a gene called FLNA, which is controlled by FOXA1, conferred a growth advantage to prostate cancer cells, which may drive early disease relapse.
“This study illustrates how we can exploit the power of genomics to make important scientific discoveries about how genetic variability in prostate cancer is controlled. We hope our findings will have [a] clinical impact by identifying more precise markers of disease recurrence and new potential drug targets,” said Dr. Rajan.
Researchers are hoping to further test whether the splice variants they have identified to be linked to cancer recurrence are useful in predicting disease relapse, and to undertake experiments to determine whether targeting these genes could represent new ways to treat prostate cancer.
Disclosure: Dr. Rajan’s work on this study was supported by funding from Cancer Research UK, Barts Charity, Orchid Charity, The Royal College of Surgeons of England, and The Urology Foundation. Dr. Cereda’s work on this study was supported by funding from the Italian Association for Cancer Research (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. For the complete list of research funders, and for full disclosures of the study authors, visit cell.com.
