Human caspase-7 is positively controlled by SREBP-1 and SREBP-2: Caspase-7 is a SREBP-1/2 target gene

International audienceStatins are lipid lowering drugs that may help limit cancer occurrence in humans. They drive blockage of the mevalonate pathway, trigger cancer cell apoptosis in vitro and reduce tumour incidence in animals. We show here that statins induced apoptosis in HGT-1 human gastric cancer cells, and this was prevented by intermediates of the cholesterol synthetic pathway. In addition, similarly to what we reported previously for caspase-2 (Logette, E., Le Jossic-Corcos, C., Masson, D., Solier, S., Sequeira-Legrand, A., Dugail, I., Lemaire-Ewing, S., Desoche, L., Solary, E. and Corcos, L. (2005) Mol Cell Biol 25, 9621-9631), caspase-7 may also be induced by statins and is under the positive control of Sterol Regulatory Element Binding Proteins-1 & -2, major activators of cholesterol and fatty acids synthesis genes, in HGT-1 cells. Knocking down these proteins strongly reduced caspase-7 mRNA and protein expression, and chromatin immunoprecipitation analyses showed that the proximal promoter region of the CASP-7 gene could bind either SREBP-1 or -2. Strikingly, cells selected to grow in the continuous presence of statins showed increased expression of caspase-7 mRNA and protein, which was maintained in the absence of statins for several weeks, suggesting that high expression of this caspase might participate in adaptation to blunting of the mevalonate pathway in this model. Together, our results show that caspase-7, as a SREBP-1/2 target, can be induced under mevalonate restricting conditions, which might help overcome its shortage