GPRC5A facilitates cell proliferation through cell cycle regulation and correlates with bone metastasis in prostate cancer

The prognosis of patients with progressive prostate cancers that are hormone refractory and/or have bone metastasis is poor. Multiple therapeutic targets to improve prostate cancer patient survival have been investigated, including orphan GPCRs. In our study, we identified G Protein‐Coupled Receptor Class C Group 5 Member A (GPRC5A) as a candidate therapeutic molecule using integrative gene expression analyses of registered data sets for prostate cancer cell lines. Kaplan–Meier analysis of TCGA data sets revealed that patients who have high GPRC5A expression had significantly shorter overall survival. PC3 prostate cancer cells with CRISPR/Cas9‐mediated GPRC5A knockout exhibited significantly reduced cell proliferation both in vitro and in vivo. RNA‐seq revealed that GPRC5A KO PC3 cells had dysregulated expression of cell cycle‐related genes, leading to cell cycle arrest at the G2/M phase. Furthermore, the registered gene expression profile data set showed that the expression level of GPRC5A in original lesions of prostate cancer patients with bone metastasis was higher than that without bone metastasis. In fact, GPRC5A KO PC3 cells failed to establish bone metastasis in xenograft mice models. In addition, our clinical study revealed that GPRC5A expression levels in prostate cancer patient samples were significantly correlated with bone metastasis as well as the patient's Gleason score (GS). Combined assessment with the immunoreactivity of GPRC5A and GS displayed higher specificity for predicting the occurrence of bone metastasis. Together, our findings indicate that GPRC5A can be a possible therapeutic target and prognostic marker molecule for progressive prostate cancer. What's new? Although androgen deprivation is effective in most prostate cancer patients, cellular pathways outside androgen receptor signaling are being explored to treat castration‐resistant cancer forms. Here the authors focus on GPRC5A, an orphan G protein‐coupled receptor, they find is overexpressed in prostate cancer cell lines. Knockout of GPRC5A decreased proliferation of a prostate cancer cell line and prevented bone metastasis in a xenograft model. In patients, GPRC5A expression correlated with shorter overall survival and bone metastasis, underscoring its clinical potential as a therapeutic or prognostic target.