Epigenetic regulation of kallikrein-related peptidases: there is a whole new world out there

Abstract

<jats:title>Abstract</jats:title><jats:p>The human kallikreins are a cluster of 15 kallikreins and kallikrein-related peptidases (KLKs). Evidence shows the involvement of KLKs in a wide range of pathophysiological processes, and underscores their potential contribution to cancer, skin and neurodegenerative disorders. The control of<jats:italic>KLK</jats:italic>expression is not fully elucidated. Understanding the mechanisms controlling<jats:italic>KLK</jats:italic>expression is an essential step towards exploring the pathogenesis of several diseases and the use of KLKs as disease biomarkers and/or therapeutic targets. Recently, epigenetic changes (including methylation, histone modification and microRNAs [miRNAs]) have drawn attention as a new dimension for controlling<jats:italic>KLK</jats:italic>expression. Reports showed the effect of methylation on the expression of<jats:italic>KLK</jats:italic>genes. This was also shown to have potential utility as a prognostic marker in cancer. miRNAs are small RNAs that control the expression of their targets at the post-transcriptional level. Target prediction showed that KLKs are potential targets of miRNAs that are dysregulated in tumors, including prostate, kidney and ovarian cancers, with downstream effect on tumor proliferation. Experimental validation remains an essential step to confirm the KLK-miRNA interaction. Epigenetic regulation of KLKs holds promise for an array of therapeutic applications in many diseases including cancer.</jats:p>

Clinical relevance of the deregulated kallikrein-related peptidase 8 mRNA expression in breast cancer: a novel independent indicator of disease-free survival

“…A recent study using massively parallel signature sequencing (MPSS) and isolated epithelial cells from BC and normal counterparts revealed that KLK8, along with KLK5, KLK7, KLK10, is among the set of genes which are significantly downregulated in the tumor epithelial transcriptome [32]. Several reports show that molecular mechanisms, such as epigenetic modifications and specifically DNA hypermethylation, may contribute to the downregulation of KLK gene expression in BC [33]. One characteristic example is the tumor-specific KLK10 exon 3 hypermethylation in BC cell lines and tissues [34,35].…”

Kallikreins as Biomarkers in Human Malignancies

“…Accumulating evidence supports that miRNAs act as posttranscriptional regulators of KLK gene expression (Pasic et al 2012;Yousef 2008). Interestingly, a study using a bioinformatics approach reported that 96 miRNAs are predicted to target one or more KLKs (Chow et al 2008).…”

“…For instance, a more recent study demonstrated that transfection of CaP cell lines, with miR-99a, miR-99b, or miR-100, resulted in both decreased expression of PSA/KLK3 and significant inhibition of cancer cell growth, suggesting a possible mechanism for regulating PSA/KLK3 in vivo (Sun et al 2011). Other experimentally validated miRNA regulators of KLK expression include miR-224 for KLK1 and KLK10, let-7f for KLK6 and KLK10, miR-516a for KLK10, miR-143 for KLK10, and miR-331-3p for KLK4 (Pasic et al 2012;White et al 2012). Nonetheless, further understanding of the miRNA-KLK axis of interaction will provide new insights into the mechanisms that control KLK deregulation in cancer and will ultimately lay the foundation for the development of novel anticancer therapeutic strategies.…”

Biomarkers for Screening, Diagnosis, and Monitoring of Ovarian Cancer

“…Recently, epigenetic changes (including methylation and miRNA regulation) were shown to control KLK expression. Target prediction showed that KLK mRNAs are potential targets of miRNAs that are dysregulated in tumors, including ovarian cancers, with downstream effect on tumor proliferation (77).…”