Nontranscriptional Role of Hif-1α in Activation of γ-Secretase and Notch Signaling in Breast Cancer

gamma-Secretase is composed of four proteins that are obligatory for protease activity: presenilin, nicastrin, Aph1, and Pen-2. Despite the progress toward understanding the function of these individual subunits, there is no information available pertaining to the modulation of gamma-secretase in response to environmental changes in cells. Here, we show that hypoxia upregulates gamma-secretase activity through a direct interaction with Hif-1 alpha, revealing an unconventional function for Hif-1 alpha as an enzyme subunit, which is distinct from its canonical role as a transcription factor. Moreover, hypoxia-induced cell invasion and metastasis are alleviated by either gamma-secretase inhibitors or a dominant-negative Notch coactivator, indicating that gamma-secretase/Notch signaling plays an essential role in controlling these cellular processes. The present study reveals a mechanism in which gamma-secretase can achieve temporal control through conditional interactions with regulatory proteins, such as Hif-1 alpha, under select physiological and pathological conditions.