NFATc1 drives Orai3 transcription and proteolysis by harnessing epigenome differences in the MARCH8 promoter

Several autonomous mechanisms regulate protein expression, such as transcription, translation, post-translational modifications, and epigenetic changes. Rarely, these processes are controlled by the same molecular player with overlapping roles. Here, we reveal that transcription factor NFATc1 regulates both transcription and degradation of the Ca²⁺ channel Orai3 in a context-dependent manner. We demonstrate that NFATc1 drives Orai3 transcription in non-metastatic pancreatic cancer cells. In invasive and metastatic pancreatic cancer cells, NFATc1 induces Orai3 lysosomal degradation by transcriptionally enhancing MARCH8 E3-ubiquitin ligase. We show that MARCH8 physically interacts with Orai3 intracellular loop eventually resulting in its ubiquitination at the N-terminal. Mechanistically, the dichotomy in the regulation of Orai3 expression emerges from the differences in MARCH8 epigenetic landscape. We uncover that MARCH8 promoter is hyper-methylated in non-metastatic cells. Importantly, we demonstrate that MARCH8 restricts pancreatic cancer metastasis by targeting Orai3 degradation, thereby highlighting the pathophysiological importance of this signaling module. Taken together, we report a unique and clinically relevant scenario wherein the same transcription factor both enhances and curtails the expression of a target protein in cancer.