The polycomb group protein EZH2 is involved in progression of prostate cancer

Abstract

Prostate cancer is a leading cause of cancer-related death in males and is second only to lung cancer. Although effective surgical and radiation treatments exist for clinically localized prostate cancer, metastatic prostate cancer remains essentially incurable. Here we show, through gene expression profiling, that the polycomb group protein enhancer of zeste homolog 2 (EZH2) is overexpressed in hormone-refractory, metastatic prostate cancer. Small interfering RNA (siRNA) duplexes targeted against EZH2 reduce the amounts of EZH2 protein present in prostate cells and also inhibit cell proliferation in vitro. Ectopic expression of EZH2 in prostate cells induces transcriptional repression of a specific cohort of genes. Gene silencing mediated by EZH2 requires the SET domain and is attenuated by inhibiting histone deacetylase activity. Amounts of both EZH2 messenger RNA and EZH2 protein are increased in metastatic prostate cancer; in addition, clinically localized prostate cancers that express higher concentrations of EZH2 show a poorer prognosis. Thus, dysregulated expression of EZH2 may be involved in the progression of prostate cancer, as well as being a marker that distinguishes indolent prostate cancer from those at risk of lethal progression.

Androgen regulation of soluble guanylyl cyclaseα1 mediates prostate cancer cell proliferation

“…C51 and C81 cells proliferate in an androgen-unresponsive manner, whereas C33 are the parental androgen-dependent cells (Igawa et al, 2002). RT-PCR analysis indicated that these cell lines express AR and PSA (Figure 3a), as reported previously (Igawa et al, 2002), as well as the prostate cancer marker EZH2 (Varambally et al, 2002) (Figure 3a). Importantly, the androgen-independent LNCaP cells also express sGCa1 mRNA to a comparable level that is found in androgen-dependent LNCaP cells (Figure 3a).…”

“…PSA expression was high in both MPC and several BPH tissues. Notably, the expression pattern of sGCa1 paralleled that of EZH2, a gene marker for prostate cancer (Varambally et al, 2002). E-cadherin expression was significantly reduced in the BPH and MPC tissues as compared to normal, consistent with the literature (Koksal et al, 2002).…”

Elevated osteonectin/SPARC expression in primary prostate cancer predicts metastatic progression

“…9,10 RAF fusions are present in about 2% of CaP associated with aggressive disease. 10 Earlier, other genes such as p53, [11][12][13] AR, 14,15 AKT/PTEN, 16 EZH2, 17 SPINK, 18 ETV1 9,19 have been shown to be associated with subsets of progressive CaP, however their use as prognostic markers in clinical setting needs to be streamlined. SPARC (secreted protein, acidic, rich in cysteine) is a secreted glycoprotein that supports the migration of CaP cells to bone and demonstrates increased expression in CaP metastatic foci and cell lines.…”

c-Jun enhancement of androgen receptor transactivation is associated with prostate cancer cell proliferation

“…Interestingly, c-Jun mRNA is only detected in our two MPC and one BPH samples (Figure 10b). Importantly, these three tissues also express elevated levels of PSA, AR, and EZH2 (Varambally et al, 2002) mRNAs (Figure 10b). …”