Phenylbutyrate interferes with the Fanconi anemia and BRCA pathway and sensitizes head and neck cancer cells to cisplatin

Background: Cisplatin has been widely used to treat head and neck cancer. One of the clinical limitations with this treatment, however, is that tumors that are initially responsive to cisplatin later acquire resistance. We have recently shown that a subset of head and neck cancer cell lines has a defective Fanconi anemia DNA damage response pathway and this defect correlates to cisplatin sensitivity. We have also shown that the histone deacetylase inhibitor phenylbutyrate sensitize human cells to cisplatin. In this study we explored whether phenylbutyrate may sensitize head and neck cancer cells by interfering with the Fanconi anemia pathway. Results: We found that the phenylbutyrate sensitizes head and neck cancer cell lines to cisplatin. This sensitization by phenylbutyrate correlated to a significant decrease in the formation of cisplatin-induced FANCD2 nuclear foci, which is a functional read out of the Fanconi anemia and BRCA ( FA/BRCA) pathway. This abrogation of the FA/BRCA pathway by phenylbutyrate was not due to loss of FANCD2 monoubiquitylation but rather correlated to a phenylbutyrate-mediated reduction in the expression of the BRCAI protein. Furthermore, we found that cancer cells defective in the FA pathway were also sensitized to cisplatin by phenylbutyrate suggesting that phenylbutyrate targets additional pathways. Conclusion: The results from this study suggest that phenylbutyrate may have therapeutic utility as a cisplatin sensitizer in head and neck cancer by inhibiting the FA/BRCA pathway through the down regulation of BRCAI as well as by an FA/BRCA-independent mechanism.