BNIP3 Promotes HIF-1α-driven Melanoma Growth by Curbing Intracellular Iron Homeostasis

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2021 May 1

PMID 33932034

Citations 36

Authors

Monica Vara-Perez

Matteo Rossi

Chris Van den Haute

Hannelore Maes

Maria Livia Sassano

Vivek Venkataramani

Bernhard Michalke

Erminia Romano

Kristine Rillaerts

Abhishek D Garg

Corentin Schepkens

Francesca M Bosisio

Jasper Wouters

Ana Isabel Oliveira

Peter Vangheluwe

Wim Annaert

Johannes V Swinnen

Jean Marie Colet

Joost J van den Oord

Sarah-Maria Fendt

Massimiliano Mazzone

Patrizia Agostinis

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

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Gieniusz E, Skrzydlewska E, Luczaj W Int J Mol Sci. 2024; 25(21).

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