# Identification of Novel Markers of Prostate Cancer Progression, Potentially Modulated by Vitamin D
## 4 Discussion
It must be kept in mind that the samples analyzed in this study come from different ethnic groups, and there was also a difference in the number of the subjects recruited (54 with respect the 548 present in our analysis) and the control samples, healthy, were subjects with benign prostatic hyperplasia (BPH). This difference could be the basis for the different results obtained in the study. In any case, the increase in mRNA levels in prostate tumor biopsies, their positive correlation with the tumor percentage and the messenger of KLK3 and their modulation by Vitamin D, need further confirmation from an in vitro experimental point of view. As regard SOX4, in our analysis we showed that the expression levels were increased in PCa patients' biopsies compared to the healthy prostate subjects. These results are totally in agreement with the recent bibliography [46; 47]. SOX4 is a transcription factor involved in the regulation of embryonic development. SOX4 is highly expressed in several human cancers of epithelial origin and is associated with a poor clinical outcome. It has been related with the loss of epithelial features and the gain of mesenchymal traits, including cell migration and invasion [48]. SOX4 knockdown repressed the cell proliferation and migration ability. Moreover, inhibition of SOX4 could reverse the epithelial-mesenchymal transition processes through up-regulation of adhesion molecules such as E-cadherin and the down-regulation of vimentin [47]. In our analysis we showed that Vitamin D was able to reduce significantly the expression of SOX4 in the _LNCaP cell line_. Noteworthy, it has been shown that the Vitamin D is able to induce E-cadherin expression in breast cancer cells by promoter demethylation [49]. Taking all of this into consideration, the Vitamin D could be able to reduce the tumor cell migration and invasion, via SOX4 down-regulation and consequently up-regulation of E-Cadherin. SMYD2 (SET and MYND domain-containing protein 2) is a histone lysine methyltransferaseenzyme, belonging to the family that contains five enzymes that share two highly conserved domains (the catalytic SET domain and the MYND domain) [50]. This enzyme is highly expressed in a variety of cancers [51; 52]. Recently, it has been shown that SMYD2 inhibits tumor suppressor proteins p53 [53] and PTEN [54]. However, to date, there has been no report on the clinical and prognostic significance of SMYD2 in patients with PCa. In our analysis, we showed that mRNA of SYMD2 is over-expressed in PCa and the treatment of the _LNCaP cell line_ with Vitamin D reduces the expression levels, but this result was not confirmed by the PCa biopsies observation. Consequently, the Vitamin D could increase PTEN expression via a down-regulation of SYMD2, and inhibit cell proliferation in PCa. In support of this hypothesis, it has been shown that the Vitamin D plays an inhibitory effect on the hepatocellular carcinoma cells proliferation through the down-regulation of HDAC and up-regulation of PTEN [55]. The expression analysis of MCCC2 in PCa biopsies, showed an over-expression on mRNA and a positive correlation with KKL3 gene expression levels and tumor %. This enzyme catalyzes the carboxylation of 3-methylcroonyl-CoA to form 3-methylglutaconyl-CoA. There is evidence that mutations of this gene is associated with 3-Methylcroonylglycinuria, an autosomal recessive disorder of leucine catabolism [56]. As regards its role in cancer, there exist only two reports that bind it to tumor development. These two reports identified MCCC2 over-expression linked to LNM PCa tissues [57] and to low-grade PCa [58]. Our results could be a good start to investigate the role of MCCC2 in cancer. In our analysis, another interesting molecule identified as potentially a marker of PCa was CCNG2. This molecule belongs to the cyclin family, and its expression is significantly higher in cell cycle-arrest [59]. The current literature suggests that CCNG2 plays an important inhibitory role in cancer initiation and progression [60].