HMGA1-pseudogenes and cancer

Abstract

Pseudogenes are DNA sequences with high homology to the corresponding functional gene, but, because of the accumulation of various mutations, they have lost their initial functions to code for proteins. Consequently, pseudogenes have been considered until few years ago dysfunctional relatives of the corresponding ancestral genes, and then useless in the course of genome evolution. However, several studies have recently established that pseudogenes are owners of key biological functions. Indeed, some pseudogenes control the expression of functional genes by competitively binding to the miRNAs, some of them generate small interference RNAs to negatively modulate the expression of functional genes, and some of them even encode functional mutated proteins. Here, we concentrate our attention on the pseudogenes of the HMGA1 gene, that codes for the HMGA1a and HMGA1b proteins having a critical role in development and cancer progression. In this review, we analyze the family of HMGA1 pseudogenes through three aspects: classification, characterization, and their possible function and involvement in cancer.

Keywords: HMGA; cancer; ceRNA; pseudogenes.

Figure 1. Structure of HMGA1Ps and their main mutations with respect to HMGA1 proteins

Diagrams illustrating the domain structures of HMGA1a, HMGA1b, HMGA1P1, HMGA1P2 and HMGA1P3. Known post-translational modifications of human HMGA1a and HMGA1b proteins impaired in HMGA1Ps are highlighted (Phosphorylation in blue, methylation in red). The three AT-hooks are in red and the acidic tail in blue.

Figure 2. HMGA1P6 and HMGA1P7 mRNA sequence shares HMGA1-targeting miRNAs

HMGA1 (top), HMGA1P6 (middle) and HMGA1P7 (bottom) mRNA sequences are shown in blue. HMGA1-targeting miRNA seed matches (red boxes) within the high homology regions are shared among HMGA1, HMGA1P6 and HMGA1P7.

Figure 3. miRNA decoy function of HMGA1Ps

In the steady state, equilibrium exists between the miRNAs and their targets HMGA1 and HMGA1Ps. By contrast, the overexpression of HMGA1P6 and HMGA1P7 results in fewer miRNAs free to bind to HMGA1, and thus HMGA1 levels increase.

Figure 4. HMGA1-p function model

In normal condition, the RNA-binding protein αCP1 stabilizes HMGA1 mRNA by binding to its 3′ UTR. In diabetes, the HMGA1-p overexpressed transcript competes with HMGA1 mRNA for the binding to αCP1, increasing the degradation of HMGA1 mRNA.