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

• Published in: Oncogene Vol. 39; no. 26; pp. 4944 - 4955
• Main Authors: Frangez, Ziva, Fernández-Marrero, Yuniel, Stojkov, Darko, Seyed Jafari, S. Morteza, Hunger, Robert E, Djonov, Valentin, Riether, Carsten
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group 25.06.2020
• Subjects: Acidification; Apoptosis; Autophagy; BAX protein; Cell death; Cell proliferation; CRISPR; Electron transport; Glycolysis; Hyperpolarization; Melanoma; Metastases; Metastasis; Mitochondria; Phagocytosis; Proteins; Respiration; Tumorigenesis; Ultraviolet radiation; Canada
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-020-1339-8

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.