BIF-1 inhibits both mitochondrial and glycolytic ATP production: its downregulation promotes melanoma growth.

Frangež, Živa; Fernández-Marrero, Yuniel; Stojkov, Darko; Seyed Jafari, S. Morteza; Hunger, Robert E.; Djonov, Valentin; Riether, Carsten; Simon, Hans-Uwe (2020). BIF-1 inhibits both mitochondrial and glycolytic ATP production: its downregulation promotes melanoma growth. Oncogene, 39(26), pp. 4944-4955. Springer Nature 10.1038/s41388-020-1339-8

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Endophilin B1, also known as BAX-interacting protein 1 (BIF-1), is part of the endophilin B protein family, and is a multifunctional protein involved in the regulation of apoptosis, autophagy, and mitochondrial morphology. The role of BIF-1 in cancer is controversial since previous reports indicated to both tumor-promoting and tumor-suppressive roles, perhaps depending on the cancer cell type. In the present study, we report that BIF-1 is significantly downregulated in both primary and metastatic melanomas, and that patients with high levels of BIF-1 expression exhibited a better overall survival. Depleting BIF-1 using CRISPR/Cas9 technology in melanoma cells resulted in higher proliferation rates both in vitro and in vivo, a finding that was associated with increased ATP production, metabolic acidification, and mitochondrial respiration. We also observed mitochondrial hyperpolarization, but no increase in the mitochondrial content of BIF-1-knockout melanoma cells. In contrast, such knockout melanoma cells were equally sensitive to anticancer drug- or UV irradiation-induced cell death, and exhibited similar autophagic activities as compared with control cells. Taken together, it appears that downregulation of BIF-1 contributes to tumorigenesis in cutaneous melanoma by upregulating mitochondrial respiration and metabolism, independent of its effect on apoptosis and autophagy.

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