# PCP4 inhibits the progression of prostate cancer through Ca2+/CAMKK2/AMPK/AR pathway

## TL;DR

PCP4 inhibits prostate cancer progression by regulating a calcium signaling pathway, and its loss is linked to poor outcomes, especially in castration-resistant prostate cancer.

## Contribution

This study reveals a novel tumor-suppressive role of PCP4 through the Ca2+/CAMKK2/AMPK/AR pathway in prostate cancer.

## Key findings

- PCP4 gene loss is frequent in prostate cancer patients and correlates with poor prognosis.
- PCP4 suppresses prostate cancer progression in vitro and in vivo.
- PCP4 inhibits cancer progression via the Ca2+/CAMKK2/AMPK/AR signaling axis.

## Abstract

The development of prostate cancer (PCa) remains a major health threat for men worldwide. Calcium/Calmodulin signaling pathway has been implicated to the initiation and progression of diverse human cancers. Loss or downregulation of Purkinje cell protein 4 (PCP4), is frequently observed in some prostate cancer patients, particularly those with castration-resistant prostate cancer (CRPC).

Public datasets were used to analyze PCP4 expression and the relationship between PCP4 expression and clinicopathological characteristics of PCa patients. Gain- and loss-of-function studies in PCa cell lines and mouse models were performed to characterize the role of PCP4 in tumor progression. A series of molecular and biochemical experiments were carried out in PCa cell lines to investigate the mechanism underlying PCP4-mediated tumor suppression.

(1) PCP4 gene loss occurs at high frequency in PCa patients, and decreased expression of PCP4 correlates with poor prognosis of PCa, particularly CRPC development; (2) TMPRSS2-ERG fusion frequently co-occurs with PCP4 deletion; (3) PCP4 suppresses prostate cancer progression in vitro and in vivo; (4) PCP4 is an androgen receptor (AR) suppressed gene; (5) PCP4 was involved in the stabilization of CAMKK2 protein; (6) PCP4 inhibits PCa progression by regulating Ca2+/CAMKK2/AMPK/AR signaling axis.

Our findings elucidate the molecular mechanism that PCP4 downregulation promotes PCa progression via Ca2+/CAMKK2/AMPK/AR pathway, highlighting its significance in CRPC development.