Antizyme inhibitor 1: a potential carcinogenic molecule

Abstract

Polyamines are multivalent and organic cations essential for cellular growth, proliferation, differentiation, and apoptosis. Increased levels of polyamines are closely associated with numerous forms of cancer. An autoregulatory circuit composed of ornithine decarboxylase (ODC), antizyme (AZ) and antizyme inhibitor (AZI) govern the intracellular level of polyamines. Antizyme binds with ODC to inhibit ODC activity and to promote the ubiquitin-independent degradation of ODC. Antizyme inhibitor binds to AZ with a higher affinity than ODC. Consequently, ODC is released from the ODC-AZ complex to rescue its activity. Antizyme inhibitor increases the ODC activity to accelerate the formation of intracellular polyamines, triggering gastric and breast carcinogenesis as well as hepatocellular carcinoma and esophageal squamous cell carcinoma development. Antizyme inhibitor 1 (AZIN1), a primary member of the AZI family, has aroused more attention because of its contribution to cancer. Even though its conformation is changed by adenosine-to-inosine (A→I) RNA editing, it plays an important role in tumorigenesis through regulating intracellular polyamines. Encouragingly, AZIN1 has been revealed to have an additional function outside the polyamine pathway so as to bypass the deficiency of targeting the polyamine biosynthetic pathway, promising to become a critical target for cancer therapy. Here, we review the latest research advances into AZIN1 and its potential contribution to carcinogenesis.

Keywords: Antizyme; antizyme inhibitor 1; carcinogenesis; ornithine decarboxylase; polyamine.

Figure 1

Historic process from basic research into understanding the biological function of antizyme inhibitor 1 (AZIN1). The protein, originally found in rat liver extract, binds antizyme (AZ) with higher affinity than ornithine decarboxylase (ODC). First thought to be an ODC derivative, AZIN1 was then proved to be a distinct protein from different aspects, including the lack of an ornithine decarboxylating activity and ubiquitin‐dependent degradation. Researchers have gradually realized that AZIN1 is associated with the risk of hepatitis B virus (HBV)‐related liver cirrhosis, or may play an important role in tumorigenesis in many different tumors, such as hepatocellular carcinoma (HCC) and esophageal squamous cell carcinoma (ESCC). miR, microRNA.

Figure 2

RNA‐edited antizyme inhibitor 1 (AZIN1) interferes with the formation of the antizyme–ornithine decarboxylase (AZ–ODC) complex, contributing to cancer development. AZIN1 and AZ regulate polyamine biosynthesis through ornithine decarboxylase (red arrows). ODC catalyzes the first step in polyamine synthesis. AZ disrupts ODC homodimers, targets ODC for degradation by the 26S proteasome in a ubiquitin‐independent manner, and inhibits polyamine uptake. Activity of AZ is further regulated by AZIN1. AZIN1 can displace ODC from the ODC–AZ complex, restoring polyamine biosynthesis by ODC. The latter is degraded by the 26S proteasome in a ubiquitin‐dependent manner. The overexpression of AZIN1 leads to a concomitant increase in ODC activity to accelerate the formation of polyamine, triggering gastric and breast carcinogenesis, and development of hepatocellular carcinoma (HCC) and esophageal squamous cell carcinoma (ESCC). RNA editing and its contribution to AZIN1 (green arrows). Adenosine‐to‐inosine editing of AZIN1 transcripts, specifically regulated by adenosine deaminase 1 acting on double‐stranded RNA (ADAR1), leads to a serine (Ser) to glycine (Gly) substitution at residue 367 of AZIN1, which is predicted to cause a conformational alteration. Compared with wild‐type (Wt‐) AZIN1 protein, the edited (Ed‐) AZIN1 binds to AZ with a higher affinity toward AZ, thus the Ed‐AZIN1 protein sequestrates AZ to block the degradation of ODC and cyclin D1 (CCND1), thus promoting cell proliferation possibly with cancer onset. Other potential roles of AZIN1 (dark blue arrows). Overexpression of AZIN1 reduces the expression levels of transforming growth factor (TGF)‐β1, TGF‐β receptor type I, and Smad3, and phosphorylation of Smad3, suppressing TGF‐β signaling and the fibrotic response. A single nucleotide polymorphism (SNP) variant in the AZIN1 gene leads to the enhanced generation of a novel alternative splice form that modifies the fibrogenic potential of hepatic stellate cells (HSCs). In addition, AZIN1 is highly expressed in cancer of the prostate, lung, and ovary. But its detailed mechanism is completely unclear.

Figure 3

Antizyme inhibitor 1 (AZIN1) interactome network. The interaction network with high confidence levels (>0.7) is shown as displayed by The European Molecular Biology Laboratory's Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) for genetically interacting proteins possibly related in function to antizyme inhibitor 1 (AZIN1). Stronger associations are represented by thicker lines. In addition to polyamine metabolism‐related regulatory proteins, including ornithine decarboxylase antizyme (OAZ)1, OAZ2, OAZ3, ubiquitin C (UBC), ornithine decarboxylase 1 (ODC1), adenosylmethionine decarboxylase 1 (AMD1), threonine synthase‐like 1 (THNSL1), and spermine synthase (SMS), fibroblast growth factor 2 (FGF2) is also correlated highly with AZIN1. SRM, spermidine synthase.