The therapeutic potential of histone deacetylase inhibitors (HDACi), shown to epigenetically regulate a variety of genes, has yet to be fully realized due to their documented pleiotropic effects in vivo. Currently, four HDACi are FDA-approved for the treatment of hematological malignancies, but their effectiveness against other types of cancers have been shown to be limited at best and, as a result, most of these clinical trials have failed. A comprehensive review of the recent literature has identified that approximately 50% of all cell lines treated with an HDACi demonstrate an increase in metastatic potential as measured by increases in migration and invasion. Of these cell lines that respond with increased metastatic potential to HDACi treatment, 60% have a gain-of-function mutation within p53 (p=0.03). As HDACi have been shown to destabilize mutant p53, they have been used in studies to examine the effects of HDACi treatment on cancers with an identified p53 mutation. This is concerning as the specific p53 mutation in these cancers is not always known, and thus treatment could potentially result in an increase in cancer cell growth. Previous work in our lab demonstrates that the human SW13 adrenal adenocarcinoma cell line, which harbors a homozygous H193Y gain-of-function mutation, does have an HDACi-induced metastatic phenotype; treated cells demonstrate significant increases in MMP activity and ~50% reduction in p53 protein expression compared to untreated cells. To investigate the role that a decrease in mutant p53 expression plays in the acquisition of metastatic characteristics we utilized stable shRNA plasmids to knock-down p53 expression in the SW13 cell line. HeLa cells, which possess a wild-type p53 gene, were used as a positive control. We found that a decrease in p53 expression alone was not sufficient to induce changes in SW13 growth or invasiveness. In fact, even though p53 expression was knocked down by ~70% in the shRNA lines, HDAC inhibition still induced the acquisition of metastatic properties in these cells. Intriguingly, while the DNA binding activity of mutant p53 was correlated with protein expression and was significantly decreased following HDAC inhibition, the same response was not observed in HeLa cells. These findings suggest that p53 status may be an important determinant of therapeutic response to HDAC inhibition.
Note: This abstract was not presented at the meeting.
Citation Format: McKale Montgomery, Elizabeth Hull. The significance of a p53 gain-of-function mutation in the acquisition of metastatic traits in the SW13 cell line [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1534. doi:10.1158/1538-7445.AM2017-1534