Identification of protein-coding genes associated with metastatic prostate cancer

Prostate cancer (PCa) is a significant cause of male mortality worldwide. Since metastases are the underlying cause of lethality, identifying markers for metastatic potential would be highly valuable. To address this issue, we set out to identify protein-coding genes with metastasis-specific expression changes in PCa. We employed a previously reported unique cohort consisting of metastases from castration-resistant prostate cancer (mCRPC) and matching primary tumors. Our comprehensive gene expression analyses identified 85 differentially expressed genes (DEGs) associated specifically with mCRPC, comprising 63 upregulated and 22 downregulated genes. Investigation of the transcription factors (TFs), such as the androgen receptor and its co-regulators FOXA1 and HOXB13, known to be important in prostate tumorigenesis, revealed their involvement in the differential expression of these genes. Furthermore, we identified enriched binding sites for nine TFs, namely EZH2, SUZ12, TLE3, TP63, CBX7, RNF2, SP140, JARID2, and CBX8, in the regulatory regions of the DEGs. Analysis of progression-free survival of prostatectomy-treated men highlighted 16 DEGs with significant prognostic value. Of these, three genes (FRMPD1, TMEM18, and ZNHIT3) were independent prognostic markers of biochemical recurrence. TMEM18 has putative androgen receptor-binding sites in its promoter region, and analysis of LNCaP cells following stimulation with dihydrotestosterone revealed a significant upregulation of TMEM18, confirming the androgen regulation of the gene. Furthermore, we confirmed the prognostic significance of TMEM18 expression at the protein level with immunohistochemistry (IHC) in a primary PCa tumor cohort. In conclusion, we identified 85 mCRPC-associated genes and showed that TMEM18 has prognostic value in early PCa.