| Abstract [eng] |
Prostate cancer (PCa) is a histologically and molecularly heterogeneous disease, which leads to unpredictable disease progression. Therefore, it is important to distinguish non–aggressive and slow– growing tumors from rapidly progressing PCa cases for optimal treatment selection. Altered histone methylation is often detected in PCa due to impaired expression of histone methylation–regulating (HM) genes. Their disregulation might be used for more accurate assessment of PCa prognosis. In this study, the expression of 7 HM genes (KDM3A, KDM4B, KDM5A, KDM5D, KDM7B, KMT1E and KMT5A) in PCa (N = 64), non–cancerous prostate tissue (NPT; N = 25) and benign prostatic hyperplasia (BPH; N = 16) samples was evaluated by quantitative PCR. Potential regulatory microRNAs were identified using in silico analysis, the expression of the selected six (miR-7-5p, miR-9-5p, miR-149-5p, miR-186-5p, miR-425-5p and miR-618) was evaluated. Expression of HM genes and miRNAs was assoaciented with the clinical–pathological patients’ characteristics. KDM5A and KMT1E expression was lower in PCa than in NPT, while KDM3A, KDM4B, KMT1E and KMT5A levels also differed from BPH (all p < 0.0500). Lower expression of KDM5A, KDM5D and KDM7B was associated with later tumor stage (pT3), for KDM5A, KDM5D and KMT1E – with more dedifferentiated tumor tissue, and higher expression of KDM5D – with TMPRSS2-ERG fusion transcript status (all p < 0.0500). Expression of KDM5A, KMT5A and KMT1E was associated with shorter survival to biochemical disease recurrence (all p < 0.0500). In univariate and multivariate Cox models, KDM5A and KMT1E had prognostic value when analyzed in both the total PCa cohort and subgroups of pT2 stage, ISUP group 2 and / or TMPRSS2-ERG positive tumors (all p > 0.0500). The sensitivity and specificity of these genes, as prognostic markers, in the total PCa cohort were 65.79% and 70.89%, respectively (both p ≤ 0.0001). From the six identified potential regulatory miRNAs, only miR-7-5p level negatively correlated with KMT5A expression (p = 0.0435). In conclusion, in this study, associations of HM gene expression with PCa and their potential utility to improve PCa diagnosis were identified. KDM5A and KMT1E genes stood out as independent predictors of BCR in the overall PCa group and in specific tumor subgroups. |
