GDF15 serves as a co-activator to enhance KISS-1 gene transcription through interacting with Sp1.

GDF15 has been recently recognized as a tumor suppressive gene. However, the underlying mechanism by which GDF15 affects breast carcinogenesis is not well understood. Here, we showed that the inhibitory effect of GDF15 on cell proliferation was dependent on the nuclear localization of the protein. Dynamic translocation of GDF15 into the nucleus altered expression of a number of genes, including KISS-1, and resulted in inhibition of cell growth and invasive behavior. Using KISS-1 promoter-driven luciferase reporter and ChIP assays, we demonstrated that, in highly malignant breast cancer cells, GDF15 directly interacts with Sp1 at the SP1-binding sites of the KISS-1 promoter, leading to upregulated KISS-1 expression. Our study indicates that nuclear GDF15 could serve as a transcriptional co-activator to mediate the expression of particular genes to reduce cell proliferation.