FDXR regulates TP73 tumor suppressor via IRP2 to modulate aging and tumor suppression
Menée sur des lignées de cellules humaines cancéreuses et à l'aide de modèles murins, cette étude met en évidence un mécanisme par lequel la ferrédoxine réductase, en agissant sur l'expression du suppresseur de tumeur TP73 via la protéine liant le fer IRP2, contrôle le processus de vieillissement et de suppression des cellules tumorales
Ferredoxin reductase (FDXR) is a mitochondrial flavoprotein that initiates electron transport from NADPH to several cytochromes P450 via two electron carriers, ferredoxin 1 (FDX1) and FDX2. FDXR is the sole ferredoxin reductase in humans and plays a critical role in steroidogenesis and biosynthesis of heme and iron–sulfur clusters. However, much less is known about the role of FDXR in cancer. Here, we showed that FDXR plays a role in tumorigenesis by modulating expression of the tumor suppressor p73. By using genetically modified mouse models, we showed recently that mice deficient in either Fdxr or Trp73 had a shorter lifespan and were prone to spontaneous tumors as compared to wild type (WT) mice. Interestingly, compound Trp73+/−;Fdxr+/− mice lived longer and developed fewer tumors when compared with Fdxr+/− or Trp73+/− mice. Moreover, we found that cellular senescence was increased in Trp73+/− and Fdxr+/− mouse embryonic fibroblasts (MEFs), which was further increased in Trp73+/−;Fdxr+/− MEFs, as compared to that in WT MEFs. Since FDXR is regulated by p73, we examined whether there was a feedback regulation between p73 and FDXR. Indeed, we found that Trp73 expression was decreased by loss of Fdxr in MEFs and that FDXR is required for p73 expression in multiple human cancer cell lines independent of p53. Mechanistically, we found that loss of FDXR, via FDX2, increased expression of iron binding protein 2 (IRP2), which subsequently repressed TP73 mRNA stability. We also demonstrated that TP73 transcript contained an iron response element in its 3’UTR, which was required for IRP2 to destabilize TP73 mRNA. Together, these data reveal a novel regulation of p73 by FDXR via IRP2 and that the FDXR‐p73 axis plays a critical role in aging and tumor suppression.