DBC1 Functions as a Tumor Suppressor by Regulating p53 Stability

•DBC1 is a tumor suppressor•Loss of DBC1 promotes tumorigenesis in a p53-dependent and SIRT1-independent manner•DBC1 stabilizes p53 through competition with Mdm2•DBC1 also stabilizes mutant p53

SummaryDBC1 (deleted in breast cancer 1), also known as CCAR2 or KIAA1967, is an important negative regulator of SIRT1 and cellular stress response. Although the Dbc1 gene localizes at a region that is homozygously deleted in breast cancer, its role in tumorigenesis remains unclear. It has been suggested to be either a tumor suppressor or an oncogene. Therefore, the function of DBC1 in cancer needs to be further explored. Here, we report that Dbc1 knockout mice are tumor prone, suggesting that DBC1 functions as a tumor suppressor in vivo. Our data suggest that the increased tumor incidence in Dbc1 knockout mice is independent of Sirt1. Instead, we found that DBC1 loss results in less p53 protein in vitro and in vivo. DBC1 directly binds p53 and stabilizes it through competition with MDM2. These studies reveal that DBC1 plays an important role in tumor suppression through p53 regulation.

Graphical AbstractFigure optionsDownload full-size imageDownload as PowerPoint slide