PKCε Promotes Oncogenic Functions of ATF2 in the Nucleus while Blocking Its Apoptotic Function at Mitochondria

The transcription factor ATF2 elicits oncogenic activities in melanoma and tumor suppressor activities in nonmalignant skin cancer. Here, we identify that ATF2 tumor suppressor function is determined by its ability to localize at the mitochondria, where it alters membrane permeability following genotoxic stress. The ability of ATF2 to reach the mitochondria is determined by PKCε, which directs ATF2 nuclear localization. Genotoxic stress attenuates PKCε effect on ATF2; enables ATF2 nuclear export and localization at the mitochondria, where it perturbs the HK1-VDAC1 complex; increases mitochondrial permeability; and promotes apoptosis. Significantly, high levels of PKCε, as seen in melanoma cells, block ATF2 nuclear export and function at the mitochondria, thereby attenuating apoptosis following exposure to genotoxic stress. In melanoma tumor samples, high PKCε levels associate with poor prognosis. Overall, our findings provide the framework for understanding how subcellular localization enables ATF2 oncogenic or tumor suppressor functions. [Display omitted] ► Genotoxic stress-induced ATF2 localization at the mitochondria promotes cell death ► PKCε mediates ATF2 nuclear localization and oncogenic transcriptional activity ► ATF2 mitochondrial localization is lost in melanomas expressing high PKCε ► Melanomas with high PKCε show resistance to genotoxic stress and poor clinical outcome In contrast to its role as a proto-oncogenic nuclear transcription factor, ATF2 promotes apoptosis by impairing mitochondrial membrane permeability. In melanoma, PKCε blocks ATF-2 nuclear export, preventing its association with mitochondria and shifting the balance from tumor suppression to progression.