Kallikreins on Steroids: Structure, Function, and Hormonal Regulation of Prostate-Specific Antigen and the Extended Kallikrein Locus

Abstract

The 15 members of the kallikrein-related serine peptidase (KLK) family have diverse tissue-specific expression profiles and putative proteolytic functions. The kallikrein family is also emerging as a rich source of disease biomarkers with KLK3, commonly known as prostate-specific antigen, being the current serum biomarker for prostate cancer. The kallikrein locus is also notable because it is extraordinarily responsive to steroids and other hormones. Indeed, at least 14 functional hormone response elements have been identified in the kallikrein locus. A more comprehensive understanding of the transcriptional regulation of kallikreins may help the field make more informed hypotheses about the physiological functions of kallikreins and their effectiveness as biomarkers. In this review, we describe the organization of the kallikrein locus and the structure of kallikrein genes and proteins. We also focus on the transcriptional regulation of kallikreins by androgens, progestins, glucocorticoids, mineralocorticoids, estrogens, and other hormones in animal models and human prostate, breast, and reproductive tract tissues. The interaction of the androgen receptor with androgen response elements in the promoter and enhancer of KLK2 and KLK3 is also summarized in detail. There is evidence that all kallikreins are regulated by multiple nuclear receptors. Yet, apart from KLK2 and KLK3, it is not clear whether all kallikreins are direct transcriptional targets. Therefore, we argue that gaining more detailed information about the mechanisms that regulate kallikrein expression should be a priority of future studies and that the kallikrein locus will continue to be an important model in the era of genome-wide analyses.

Kallikrein-Related Peptidase 14 Acts on Proteinase-Activated Receptor 2 to Induce Signaling Pathway in Colon Cancer Cells

“…Although several studies indicating that KLK expression in many cancers, including breast, ovarian, prostate, and lung cancers, is under multiple regulatory mechanisms, such as hormonal and epigenetic mechanisms, 41 the mechanism whereby the KLK14 gene is switched on in colon cancer is unknown. It is likely that this ectopic expression can probably be controlled by common regulatory mechanisms, as in the other epithelial cancers.…”

Enhancer RNAs participate in androgen receptor-driven looping that selectively enhances gene activation

“…To address this, we used the chromosome conformation capture (3C) assay to study the spatial interaction of the KLK3/2 loci. It should be noted that the KLK2 promoter contains an ARE I that shares over 80% sequence homology with the ARE I in the KLK3 promoter (20). Indeed, DHT induces KLK2 transcription and the interaction between the anchor and fragment D and E by twofold to threefold (Fig.…”

“…enhancer, also defined as the androgen response element III (ARE III) (20), was marked by AR, H3K27ac, and H3K4me1, implying that this region is transcriptionally active (Fig. 1A).…”

A gene signature identified using a mouse model of androgen receptor‐dependent prostate cancer predicts biochemical relapse in human disease

“…Ten of the 13 members of the androgen-responsive and mouse-specific kallikrein Klk1b family were increased in AR-E231G prostates, suggesting that these factors could be a useful marker of prostate cancer initiation in mouse models. 37 Ingenuity pathways analysis (IPA) was used to identify biological pathways enriched in the AR-E231G gene set (Fig. 1b).…”