Iron Regulatory Protein 2 Exerts its Oncogenic Activities by Suppressing TAp63 Expression

Abstract

Iron regulatory protein 2 (IRP2) is a key regulator of iron homeostasis and is found to be altered in several types of human cancer. However, how IRP2 contributes to tumorigenesis remains to be elucidated. In this study, we sought to investigate the role of IRP2 in tumorigenesis and found that IRP2 promotes cell growth by repressing TAp63, a member of p53 tumor suppressor family. Specifically, we found that IRP2 overexpression decreased, whereas IRP2 deficiency increased, TAp63 expression. We also showed that the repression of TAp63 by IRP2 was independent of tumor suppressor p53. To uncover the molecular basis, we found that IRP2 stabilized TAp63 mRNA by binding to an iron response element in the 3'UTR of p63 mRNA. To determine the biological significance of this regulation, we showed that IRP2 facilitates cell proliferation at least in part via repressing TAp63 expression. Moreover, we found that IRP2 deficiency markedly alleviated cellular senescence in TAp63-deficient mouse embryo fibroblasts. Together, we have uncovered a novel regulation of TAp63 by IRP2 and our data suggest that IRP2 exerts its oncogenic activities at least in part by repressing TAp63 expression. Implications: We have revealed a novel regulation of TAp63 by IRP2 and our data suggest that IRP2 exerts its oncogenic activities at least in part by repressing TAp63 expression.

The foggy world(s) of p63 isoform regulation in normal cells and cancer

“…Clinically, p63 has value in identifying malignancy and for tumour classification, and isoform‐specific ΔNp63 antibodies are superior to assessing total p63 in many situations (reviewed in ref 249). In addition, although not well studied in clinical material, TAp63 provides prognostic information [15,18,249–251] and requires more study in lymphomas and lymphocytes (including tumour‐infiltrating lymphocytes) to understand its prognostic impact and opportunities for therapy. Advances in understanding p63 isoforms and their regulation will inevitably lead to new diagnostic, prognostic and therapeutic opportunities for cancer and other pathological conditions.…”

The p53 Family: A Role in Lipid and Iron Metabolism

“…Recent studies in our lab revealed a potential mechanism through which iron overload can influence p63/p73 mRNA stability and protein expression. We showed that TAp63 expression can be repressed by IRP2 and likewise, IRP2 deficiency lead to increased expression of TAp63 ( Zhang et al, 2020 ). Additionally, we showed that IRP2 binds to the IRE in p63 mRNA to regulates its stability ( Zhang et al, 2020 ).…”

“…We showed that TAp63 expression can be repressed by IRP2 and likewise, IRP2 deficiency lead to increased expression of TAp63 ( Zhang et al, 2020 ). Additionally, we showed that IRP2 binds to the IRE in p63 mRNA to regulates its stability ( Zhang et al, 2020 ). Similarly, we found that FDXR regulates p73 mRNA stability through IRP2 ( Zhang et al, 2020 ).…”

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.…”