Fatty acid synthase (FASN) is the sole mammalian enzyme capable of de novo lipid synthesis. Except in lipogenic tissues, FASN expression and activity is largely repressed by dietary fat. In contrast, abnormally elevated FASN expression and activity have been found in many types of human cancers. In vivo and in vitro studies showed that inhibition of FASN led to selective cytostatic and cytotoxic effect in cancer tissues and cells, with minimal adverse effect towards normal tissues. Clearly, FASN is no longer just an anabolic protein, but also provides growth and survival advantages to tumor cells. It has also been found that ectopic overexpression of FASN causes resistance to DNA-damaging drugs including doxorubicin, mitoxantrone, and etoposide as well as to ionizing radiation (IR), but not to non-genotoxic drugs such as vinblastine and paclitaxel. This finding suggests that FASN overexpression may regulate the DNA damage/repair pathway to help breast cancer cells survive DNA-damaging treatments. In this study, we tested this hypothesis. We found that FASN expression had profound effect on the rate of γ-H2AX clearance after exposure to IR or doxorubucin. While knocking down FASN delayed γ-H2AX clearance, FASN overexpression increased γ-H2AX clearance. Using neutral comet assay, we also found that double strand DNA break (DSB) induced by doxorubicin was increased by knocking down FASN expression but attenuated by increasing FASN expression. Furthermore, using a host-cell reactivation based assay, we showed that FASN overexpression significantly increased Non-homologous End Joining DNA repair activity. Together, we conclude that FASN likely plays an important role in regulating DSB repair in cancer cells.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2124. doi:1538-7445.AM2012-2124