METAREPAIR · INVESTIGATING THE IMPACT OF NUTRITIONAL METABOLISM ON DNA DAMAGE REPAIR IN CANCER

INVESTIGATING THE IMPACT OF NUTRITIONAL METABOLISM ON DNA DAMAGE REPAIR IN CANCER

In prostate cancer (PCa), loss of genomic fidelity is one of the drivers of tumorigenesis, but little is known on the mechanisms contributing to genomic instability during cancer progression. A growing amount of epidemiological and preclinical data is showing that diet plays a key role in cancer aetiology. Preliminary data indicates that those diets, such as western-style diet, that favour tumorigenesis exert their tumorigenic potential by generating inside the cells a metabolic environment that promotes genomic instability and, therefore, favours the structural genomic rearrangements necessary to promote PCa progression. I hypothesize that this can occur in part through a breach in the surveillance systems that normally guard genomic integrity, and in part through a loss of efficiency in the DNA damage repair machinery, resulting in incomplete or defective repair of DNA lesions. With METAREPAIR, I set out to investigate one specific set of cellular metabolites, part of the one carbon metabolism pathway, which contribute to the regulation of the epigenetic and epitranscriptomic landscape of the cells and can therefore indirectly affect the DNA repair capacity of cancer cells. The results of METAREPAIR can contribute to better understand the complex link between cancer and diet. This, in turn, can be used to better design cancer-protective diets, or diets that could be used as adjuvant-therapy during radio or chemotherapies. The overarching scientific goal of METAREPAIR was to deconvolute the link between nutritional metabolic alterations and genomic instability in PCa cells and leverage this link as a precision nutrition approach to sensitize PCa tumours to DNA-damaging therapies. The scientific aims were articulated into 3 independent objectives: 1) Define the effect of one carbon metabolites modulation on DNA damage repair (DDR) through the regulation of histone methylation; 2) Define the effect of one carbon metabolites modulation on DDR through the regulation of RNA methylation; 3) Exploit the impact of 1Cmet modulation on DDR to sensitize PCa tumours to DNA-damaging therapies. The results of the DDR time course showed that methionine starvation resulted in decreased 53BP1 foci formation, but this was not coupled with any change in DNA damage load. In line with these observations, the GFP reporter-assays indicated that DNA repair pathway choice was unaffected by 1Cmet manipulation. The same negative results were observed when PCa cells were treated with the PARP inhibitor Olaparib, which was used as an alternative mean to induce DNA damage. Taken together, these results suggest that 1C met manipulation does not sensitize PCa cells to IR-induced DNA damage.

Data: CORDIS, © European Union