Search for Novel Diagnostic Biomarkers of Prostate Inflammation-Related Disorders: Role of Transglutaminase Isoforms as Potential Candidates

Abstract

Investigations on prostate inflammation-related disorders, including acute and chronic prostatitis, chronic pelvic pain syndrome, benign prostate hyperplasia (BPH), and prostate cancer (PCa), are still ongoing to find new, accurate, and noninvasive biomarkers for a differential diagnosis of those pathological conditions sharing some common macroscopic features. Moreover, an ideal biomarker should be useful for risk assessment of prostate inflammation progression to more severe disorders, like BPH or PCa, as well as for monitoring of treatment response and prognosis establishment in carcinoma cases. Recent literature evidence highlighted that changes in the expression of transglutaminases, enzymes that catalyze transamidation reactions leading to posttranslational modifications of soluble proteins, occur in prostate inflammation-related disorders. This review focuses on the role specifically played by transglutaminases 4 (TG4) and 2 (TG2) and suggests that both isoenzymes hold a potential to be included in the list of candidates as novel diagnostic biomarkers for the above-cited prostate pathological conditions.

Figure 1

TG4 and TG2 alternative splicing. (a) Alternative splicing in TG4 transcript occurs at the N-terminal domain, leading to the formation of three variants. The asterisks indicate the exon interested by the splicing mechanism for each variant. (b) The sequence corresponding to the catalytic core or to the β-barrel domains of TG2 is involved in the splicing events. The intron retention mechanism that leads to the formation of TG2_v2 affects the exon 10. Shown here is the GTP/GDP binding site that involves also few amino acids (aa) in the exon 4 (arrow). In yellow is the conserved sequence of the catalytic core, including the cysteine (in bold).

Figure 2

Schematic of the alternative NF-κB activation pathway mediated by TG2. Inflammatory signals induce TG2 activation and interaction with the cytosolic inactive NF-κB complex, composed of the transcriptionally active p50 and p65 subunits and the inhibitory IκBα subunit. TG2 binding to IκBα leads to IκBα polymerization and release from NF-κB complex, followed by degradation of IκBα aggregates via a proteasome-independent pathway. The active p50/p65 heterodimer complex, associated with TG2, translocates to the nucleus where it binds to the NF-κB consensus sequence (GGGRNNYYCC) present in the promoter region of several genes involved in inflammation as well as in tumorigenesis.