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BNIP3 promotes HIF‐1α‐driven melanoma growth by curbing intracellular iron homeostasis
Author(s) -
VaraPérez Mónica,
Rossi Matteo,
Van den Haute Chris,
Maes Hannelore,
Sassano Maria Livia,
Venkataramani Vivek,
Michalke Bernhard,
Romano Erminia,
Rillaerts Kristine,
Garg Abhishek D,
Schepkens Corentin,
Bosisio Francesca M,
Wouters Jasper,
Oliveira Ana Isabel,
Vangheluwe Peter,
Annaert Wim,
Swinnen Johannes V,
Colet Jean Marie,
van den Oord Joost J,
Fendt SarahMaria,
Mazzone Massimiliano,
Agostinis Patrizia
Publication year - 2021
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.2020106214
Subject(s) - library science , biology , computer science
BNIP3 is a mitophagy receptor with context‐dependent roles in cancer, but whether and how it modulates melanoma growth in vivo remains unknown. Here, we found that elevated BNIP3 levels correlated with poorer melanoma patient’s survival and depletion of BNIP3 in B16‐F10 melanoma cells compromised tumor growth in vivo . BNIP3 depletion halted mitophagy and enforced a PHD2‐mediated downregulation of HIF‐1α and its glycolytic program both in vitro and in vivo . Mechanistically, we found that BNIP3‐deprived melanoma cells displayed increased intracellular iron levels caused by heightened NCOA4‐mediated ferritinophagy, which fostered PHD2‐mediated HIF‐1α destabilization. These effects were not phenocopied by ATG5 or NIX silencing. Restoring HIF‐1α levels in BNIP3‐depleted melanoma cells rescued their metabolic phenotype and tumor growth in vivo , but did not affect NCOA4 turnover, underscoring that these BNIP3 effects are not secondary to HIF‐1α. These results unravel an unexpected role of BNIP3 as upstream regulator of the pro‐tumorigenic HIF‐1α glycolytic program in melanoma cells.