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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.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC7749625 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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

Zhang Yanhong Y Feng Xiuli X Zhang Jin J Chen Xinbin X

Molecular cancer research : MCR 20200410 7

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 <i>IRP2</i> deficiency increased, TAp63 expression ...[more]

PMID: 32276991

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Project description:Background and aimsRas-like (Ral) small guanosine triphosphatases (GTPases), RalA and RalB, are proto-oncogenes directly downstream of Ras and cycle between the active guanosine triphosphate-bound and inactive guanosine diphosphate-bound forms. RalGTPase-activating protein (RalGAP) complex exerts a negative regulation. Currently, the role of Ral up-regulation in cancers remains unclear. We aimed to examine the clinical significance, functional implications, and underlying mechanisms of RalA signaling in HCC.Approach and resultsOur in-house and The Cancer Genome Atlas RNA sequencing data and quantitative PCR data revealed significant up-regulation of RalA in patients' HCCs. Up-regulation of RalA was associated with more aggressive tumor behavior and poorer prognosis. Consistently, knockdown of RalA in HCC cells attenuated cell proliferation and migration in vitro and tumorigenicity and metastasis in vivo. We found that RalA up-regulation was driven by copy number gain and uncovered that SP1 and ETS proto-oncogene 2 transcription factor cotranscriptionally drove RalA expression. On the other hand, RalGAPA2 knockdown increased the RalA activity and promoted intrahepatic and extrahepatic metastasis in vivo. Consistently, we observed significant RalGAPA2 down-regulation in patients' HCCs. Intriguingly, HCC tumors showing simultaneous down-regulation of RalGAPA2 and up-regulation of RalA displayed a significant association with more aggressive tumor behavior in terms of more frequent venous invasion, more advanced tumor stage, and poorer overall survival. Of note, Ral inhibition by a Ral-specific inhibitor RBC8 suppressed the oncogenic functions in a dose-dependent manner and sensitized HCC cells to sorafenib treatment, with an underlying enhanced inhibition of mammalian target of rapamycin signaling.ConclusionsOur results provide biological insight that dysregulation of RalA signaling through dual regulatory mechanisms supports its oncogenic functions in HCC. Targeting RalA may serve as a potential alternative therapeutic approach alone or in combination with currently available therapy.

Project description:The TP63 gene encodes two major protein variants; TAp63 contains a p53-like transcription domain and consequently has tumor suppressor activities whereas ΔNp63 lacks this domain and acts as an oncogene. The two variants show distinct expression patterns in normal tissues and tumors, with lymphocytes and lymphomas/leukemias expressing TAp63, and basal epithelial cells and some carcinomas expressing high levels of ΔNp63, most notably squamous cell carcinomas (SCC). Whilst the transcriptional functions of TAp63 and ΔNp63 isoforms are known, the mechanisms involved in their regulation are poorly understood. Using squamous epithelial cells that contain high levels of ΔNp63 and low/undetectable TAp63, the DNA demethylating agent decitabine (5-aza-2'-deoxycytidine, 5-dAza) caused a dose-dependent increase in TAp63, with a simultaneous reduction in ΔNp63, indicating DNA methylation-dependent regulation at the isoform-specific promoters. The basal cytokeratin KRT5, a direct ΔNp63 transcriptional target, was also reduced, confirming functional alteration of p63 activity after DNA demethylation. We also showed high level methylation of three CpG sites in the TAP63 promoter in these cells, which was reduced by decitabine. DNMT1 depletion using inducible shRNAs partially replicated these effects, including an increase in the ratio of TAP63:ΔNP63 mRNAs, a reduction in ΔNp63 protein and reduced KRT5 mRNA levels. Finally, high DNA methylation levels were found at the TAP63 promoter in clinical SCC samples and matched normal tissues. We conclude that DNA methylation at the TAP63 promoter normally silences transcription in squamous epithelial cells, indicating DNA methylation as a therapeutic approach to induce this tumor suppressor in cancer. That decitabine simultaneously reduced the oncogenic activity of ΔNp63 provides a "double whammy" for SCC and other p63-positive carcinomas. Whilst a variety of mechanisms may be involved in producing the opposite effects of DNA demethylation on TAp63 and ΔNp63, we propose an "either or" mechanism in which TAP63 transcription physically interferes with the ability to initiate transcription from the downstream ΔNP63 promoter on the same DNA strand. This mechanism can explain the observed inverse expression of p63 isoforms in normal cells and cancer.

Dataset Information

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

Publications

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

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