Mdm2 is a target and mediator of IRP2 in cell growth control

Abstract

Iron is an essential element to all living organisms and plays a vital role in many cellular processes, such as DNA synthesis and energy production. The Mdm2 oncogene is an E3 ligase and known to promote tumor growth. However, the role of Mdm2 in iron homeostasis is not certain. Here, we showed that Mdm2 expression was increased by iron depletion but decreased by iron repletion. We also showed that Iron Regulatory Protein 2 (IRP2) mediated iron‐regulated Mdm2 expression. Specifically, Mdm2 expression was increased by ectopic IRP2 but decreased by knockdown or knockout of IRP2 in human cancer cells as well as in mouse embryonic fibroblasts. In addition, we showed that IRP2‐regulated Mdm2 expression was independent of tumor suppressor p53. Mechanistically, we found that IRP2 stabilized Mdm2 transcript via binding to an iron response element (IRE) in the 3ʹUTR of Mdm2 mRNA. Finally, we showed that Mdm2 is required for IRP2‐mediated cell proliferation and Mdm2 expression is highly associated with IRP2 in both the normal and cancerous liver tissues. Together, we uncover a novel regulation of Mdm2 by IRP2 via mRNA stability and that the IRP2‐Mdm2 axis may play a critical role in cell growth.

Epigenetic Silencing of PTEN and Epi-Transcriptional Silencing of MDM2 Underlied Progression to Secondary Acute Myeloid Leukemia in Myelodysplastic Syndrome Treated with Hypomethylating Agents

“…Taking into account the oncogenic role of MDM2 reported in del(5q) MDS and AML, we further propose a functional switch of MDM2 from oncogenic to tumor suppressive during HMA resistance, with loss of MDM2 being attributed to RNA hypomethylation ( Figure 5 ) [ 50 , 51 ] In addition, the truncated MDM2 observed in our study only retains the 3′ UTR and is in-keeping with a long non-coding RNA without open reading frame [ 55 ]. It has been shown that the iron-binding protein IRP2 binds to the 3′UTR of MDM2, which results in stabilization of the MDM2 transcript [ 56 ]. We postulate that there is a competitive binding between normal MDM2 and the truncated MDM2 for IRP2, resulting in MDM2 mRNA instability and degradation during HMA resistance.…”

Epigenetic Silencing of PTEN and Epi-transcriptional Silencing of MDM2 Underlied Resistance to Hypomethylating Agents in Myelodysplastic Syndrome

“…Taking into account the oncogenic role of MDM2 reported in del(5q) MDS and AML, we further propose a functional switch of MDM2 from oncogenic to tumor suppressive during HMA resistance, with loss of MDM2 being attributed to RNA hypomethylation (Figure 5) 49,50 In addition, the truncated MDM2 observed in our study only retains the 3' UTR and is in-keeping with a long non-coding RNA without open reading frame 54 . It has been shown that the iron-binding protein IRP2 binds to the 3'UTR of MDM2, which results in stabilization of the MDM2 transcript 55 . We postulate that there is a competitive binding between normal MDM2 and the truncated MDM2 for IRP2, resulting in MDM2 mRNA instability and degradation during HMA resistance.…”

The Role of Iron in Cancer Progression

“…IRP2 is also regulated by the deubiquitinating enzyme OTUD1, which promotes TFR1-mediated iron transport via deubiquitinating and stabilizing IRP2, leading to increased ROS production, and the downregulation of OTUD1 has been found to be highly correlated with poor prognosis of colorectal cancer ( 80 ); A study linking a clinical trial of JBR.10 (n = 131) with a sample of patients from the University of Toronto Health Network (n = 181) indicated that the effect of the 15q25 mutation on lung cancer risk was associated with increased expression of IREB2 ( 40 ); Another large-scale case-control study confirmed that the miRNA binding site SNP rs1062980 in the IREB2 3’ UTR might potentially alter IREB2 expression to reduce the risk of lung cancer by regulating the binding of miR-29a ( 41 ). Additionally, the specific cause of dysregulation of IRP1/2 may be related to inhibition of TAp63 and activation of MDM2 ( 81 , 82 ).Notably, chemotherapy and targeted-therapy may work together to disrupt IRP-mediated iron regulation, like Horniblow et al. found that the MEK inhibitor trimetinib consistently inhibited IRP2 expression in four colorectal cell lines, resulting in decreased TFR1 expression and increased ferritin expression ( 83 ); Miyazawa et al.…”