Evidence of YYls oncogenic regulation in prostate cancer

Many lines of evidence support an oncogenic role of YY1. Most functions of YY1 discussed above contribute to this role in prostate cancer. Importantly, the overexpression of YY1 in prostate cancer augments the oncogenic effects caused by its regulated pathways. We allocate the role of YY1 in prostate oncogenesis into two categories based on the different regulatory mechanisms.

5.1. Transcriptional regulation

As a transcription factor, YY1 generally activates the expression of oncogenic or proliferative genes and inhibits those with tumor suppressive functions [105].

The Rex1 protein is a marker of both mouse and human embryonic stem cells and exhibits reduced expression in prostate cancer cells compared to normal prostate epithelial cells [106]. YY1 positively regulates Rex1 expression in normal human prostate epithelial cells, but this regulation is not observed in prostate cancer cells, suggesting that YY1 transcrip-tional activity may be altered during transformation [106].

Prostate stem cell antigen (PSCA) is differentially regulated during prostate oncogenesis and its expression is correlated with the development of malignant human prostate cancer. YY1 cooperates with androgen receptor (AR) to regulate PSCA expression [107]. Two YY1 consensus sites have been identified in the PSCA promoter and YY1 is overall essential to androgen-mediated PSCA upregulation in prostate epithelial cell lines. This suggests that YY1 contributes to prostate cancer progression by modulating genes such as PSCA (Figure 2) [107].

YY1 can act as a transcription coactivator to promote gene expression. We demonstrated that the expression of prostate-specific antigen (PSA) in prostate cancer cells is dependent on YY1 [70]. This effect is unaltered when the YY1 binding site in the PSA promoter is mutated, but lost when the direct YY1-AR interaction is disrupted. Since YY1-DNA association is unnecessary for YY1-mediated PSA transcription, YY1 acts as a coactivator in promoting PSA gene expression. We mapped the AR binding domain to the C-terminus of YY1 where its DNA binding site resides, suggesting that YY1 unlikely interacts simultaneously with the

PSA promoter and AR [70]. Elevated PSA levels serve as a diagnostic marker of prostate cancer development, and androgen hormones, which bind to AR and stimulate its activity, are known to facilitate prostate cancer progression [108]. The positive regulation of PSA expression by YY1 suggests its diagnostic and prognostic value in prostate cancer therapies (Figure 2).

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Figure 2. An Overview of Several YY1-Involved Signaling Pathways in Prostate Cancer; YY1 inhibits apoptosis by repressing DR5 and Fas receptors. YY1 and androgen receptor (AR) cooperate to activate expression of prostate specific antigen (PSA) and prostate stem cell antigen (PSCA), both of which contribute to prostate oncogenesis. HOXB13 inhibits prostate cancer cell growth by antagonizing AR signaling. YY1 represses HOXB13 transcription, thereby relieving growth suppression. The growth hormone tumor necrosis factor (TNF)-a enhances NF-KB-mediated YY1 expression and AR activity, promoting cell survival and growth. Overall, YY1 function and regulation support its oncogenic role in prostate cancer development and progression.

Figure 2. An Overview of Several YY1-Involved Signaling Pathways in Prostate Cancer; YY1 inhibits apoptosis by repressing DR5 and Fas receptors. YY1 and androgen receptor (AR) cooperate to activate expression of prostate specific antigen (PSA) and prostate stem cell antigen (PSCA), both of which contribute to prostate oncogenesis. HOXB13 inhibits prostate cancer cell growth by antagonizing AR signaling. YY1 represses HOXB13 transcription, thereby relieving growth suppression. The growth hormone tumor necrosis factor (TNF)-a enhances NF-KB-mediated YY1 expression and AR activity, promoting cell survival and growth. Overall, YY1 function and regulation support its oncogenic role in prostate cancer development and progression.

More evidence has been demonstrated to show how YY1-mediated transcriptional repression contributes to the oncogenic progression and therapeutic response of prostate cancer.

The homeobox gene HOXB13 suppresses prostate cancer cell growth by negatively regulating AR and T-cell factor (TCF) -4 signaling (Figure 2) [109, 110]. YY1 binds to the HOXB13 promoter and represses its expression through recruiting HDAC4, suggesting that YY1 releases HOXB13-mediated growth arrest of prostate cancer cells [8].

Fas receptor and DR5 are two death receptors regulating extrinsic apoptotic pathways. YY1 negatively regulates the expression of these two receptors (Figure 2) [111, 112]. Nitric oxide (NO) acts as an intracellular second messenger to modify gene expression, including upregulating Fas receptor. The underlying mechanism of this regulation is through NO-induced S-nitrosylation of YY1 and the consequently reduced YY1 DNA binding affinity. This abolishes YY1 mediated Fas receptor gene repression and sensitizes prostate cancer cells to apoptotic stimuli [111]. A similar mechanism has also been reported in the regulation of YY1 by Rituximab, a synthetic antibody used in the treatment of multiple cancers, including prostate cancer [112]. YY1 inhibits DR5 expression; thus elevated YY1 levels in prostate cancer confer therapeutic resistance to tumor cells through downregulating DR5. Rituximab inhibits both DNA binding and expression of YY1, which consequently activates DR5 gene expression and sensitizes TRAIL-induced apoptosis.

5.2. The regulation of YY1 in prostate cancer-related mechanisms

In addition to the growth stimuli indicated above, YY1 expression is regulated by signaling pathways directly involved in prostate oncogenesis.

NF-kB contributes to prostate cancer development through its constitutive activation of AR expression and therefore serves as a prognostic marker of prostate cancer [113-115]. NF-kB directly binds to the YY1 promoter to enhance YY1 expression (Figure 2) [116]. Thus, genetic deletion of the p65 subunit of NF-kB was associated with decreased YY1 mRNA and protein levels [117]. Consistently, the growth hormone tumor necrosis factor (TNF) -a, an activator of NF-kB transcriptional activity, stimulates NF-KB-mediated YY1 expression in prostate cancer PC-3 cells (Figure 2) [117].

Transforming growth factor (TGF) -p3 is a commonly upregulated growth factor in cancers. A recent study revealed differential regulatory effects of TGF-p3 on YY1 expression in various prostate cell lines [118]. While TGF-p3 promotes YY1 expression in benign prostatic hyperplasia cells, this effect is diminished in LNCaP cells and reversed in DU145 cells. Consistent with other studies, these altered YY1 expression levels inversely correlated to p53 levels [47-49].

The contribution of Akt-mediated signaling pathways to prostate cancer development is well documented. Akt was reported to mediate YY1 phosphorylation and its cytoplasmic translocation, although the target residue(s) and whether the effect is direct or not remain unclear [45]. Tumor suppressor PTEN inhibits the proliferative regulation of Akt through antagonizing its phosphorylation [119-121]. Recent studies demonstrated PTEN-mediated YY1 downregulation through inhibiting PI3K/Akt signaling [52, 122].

Consistent with these mechanistic studies, YY1 was suggested as a biomarker of prostate cancer. A study using a prostate cancer tissue microarray consisting of 1364 representative tissues from 246 hormone-naive prostate cancer patients demonstrated that YY1 levels were increased in tumors of intermediate to high morphologic grades, indicating its upre-gulation throughout the progression of prostate cancer [3]. Interestingly, YY1 immunohis-tochemical staining was observed in both nucleus and cytoplasm in tissues of prostate cancer and prostatic intraepithelial neoplasia, consistent with the cytoplasmic localization of YY1 demonstrated in other cells [98]. In another study, YY1 was one of several differentially expressed proteins in prostate cancer in comparison to benign prostatic hyperplasia and contributed to upregulated transcriptional networks [76].

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