"Determining the kallikrein-related peptidase 4-regulated degradome and transcriptome in the prostate cancer microenvironment"

Prostate cancer is a leading cause of male cancer-related deaths in developed countries. While the gland-lining prostate cells transform to become cancerous, these cells must transform the surrounding microenvironment to facilitate cancer progression. Novel anti-cancer therapies are required, which need to target factors driving the transformation of both the tumour and its microenvironment.

Kallikrein-related peptidase 4 (KLK4) is a secreted protease, which is over-produced by prostate cancer cells and in a pre-cancerous pathology, whereupon transformation of the tumour microenvironment initiates. KLK4 induces some cancer-promoting cellular functions, in vitro, but the underlying mechanisms are poorly defined. Further, KLK4 function in the tumour microenvironment is poorly understood.

To determine the effects of KLK4 on prostate cancer cells and the surrounding microenvironment, high-throughput technologies were used to identify KLK4 substrates (‘degradome’) and KLK4-regulated genes (‘transcriptome’) in both cell compartments. Seventy-nine novel substrates and one established KLK4 substrate were identified. KLK4 activated a key signalling pathway involved in transformation of the tumour microenvironment and also cleaved/regulated factors involved in additional cancer-promoting functions.

This study constitutes the most comprehensive analysis of the KLK4 degradome and transcriptome in prostate cancer to date, and suggests KLK4 to be a promising anti-cancer target.