BNIP3 promotes HIF-1α-driven melanoma growth by curbing intracellular iron homeostasis.
Animals
Apoptosis
/ genetics
Cell Line, Tumor
Computational Biology
Female
Gas Chromatography-Mass Spectrometry
Humans
Hypoxia-Inducible Factor 1, alpha Subunit
/ metabolism
Immunoblotting
Immunohistochemistry
Magnetic Resonance Spectroscopy
Melanoma
/ metabolism
Membrane Proteins
/ metabolism
Mice
Mice, Inbred C57BL
Mitochondrial Proteins
/ metabolism
Signal Transduction
/ genetics
BNIP3
HIF-1α
ferritinophagy
melanoma
metabolism
Journal
The EMBO journal
ISSN: 1460-2075
Titre abrégé: EMBO J
Pays: England
ID NLM: 8208664
Informations de publication
Date de publication:
17 05 2021
17 05 2021
Historique:
revised:
22
02
2021
received:
10
07
2020
accepted:
24
02
2021
pubmed:
2
5
2021
medline:
16
11
2021
entrez:
1
5
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33932034
doi: 10.15252/embj.2020106214
pmc: PMC8126921
doi:
Substances chimiques
BNip3 protein, mouse
0
HIF1A protein, human
0
Hypoxia-Inducible Factor 1, alpha Subunit
0
Membrane Proteins
0
Mitochondrial Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e106214Informations de copyright
© 2021 The Authors. Published under the terms of the CC BY NC ND 4.0 license.
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