The focus of scientific research into BHD Syndrome should centre on elucidating the biological role of folliculin (FLCN) within the cell, but a recent paper in the European Journal of Cancer has brought the topic of DNA repair enzymes into light.
The multi-step model for tumourigenesis proposes that the tumourigenic growth of malignant cells from normal tissue is preceded by the accumulation of genetic errors in a sequential fashion, where each step provides a positive growth advantage to the nascent tumour cells, allowing them to break free from the normal regulatory constraints that determine normal growth and differentiation. Habib et al, (2010)* have shown that rapamycin treated HK2 cells, mouse Tsc-deficient cells and human VHL-deficient cells leads to increased protein and promoter activity of the DNA repair enzyme OGG1 and that this mediated via an increase in expression of the transcription factor, NF-YA. This increase in OGG1 activity is thought to suppress the development of further tumours in treated cells and the authors speculate that a rapamycin-mediated mechanism of enhancing DNA repair in cancer cells may explain the inhibition of further tumourigenic growth for as long as rapamycin is applied.
DNA repair enzymes such as OGG1 repair damage to DNA bases caused by oxidative damage, which may occur because of normal aerobic metabolism or exposure to external environmental carcinogens. Whilst such damage itself is not immediately pathogenic, it results in a mutator phenotype since the ‘increasing impairment in DNA repair contributes to the genomic instability, and consequently increases the risk of cancer’. Indeed, a familial colorectal polyposis syndrome know as MAP is caused by bialleic inactivation of the DNA repair enzyme MUTYH, so as ‘family’ of proteins, their significance in cancer aetiology is not to be underestimated.
Given the phenotypic overlap between BHD Syndrome, VHL and TSC, as well as the role implicated for FLCN in mTOR signalling (and subsequent therapeutic benefit of rapamycin analogs) I wonder whether DNA repair enzymes may have a similar role in BHD associated tumourigenesis.
*Habib SL, et al. Novel mechanism of reducing tumourigenesis: Upregulation of the DNA repair enzyme OGG1 by rapamycin-mediated AMPK activation and mTOR inhibition.Eur J Cancer. 2010 Jul 23.