The gene encoding the prostatic tumor suppressor PSP94 is a target for repression by the Polycomb group protein EZH2

Abstract

BelgiumPSP94, for prostatic secretory protein of 94 amino acids, is secreted by the prostate gland and functions as a suppressor of tumor growth and metastasis. The expression of PSP94 is lost in advanced, hormone-refractory prostate cancer and this correlates with an increased expression of the Polycomb protein EZH2 (enhancer of zeste homolog 2), which represses transcription via trimethylation of histone H3 on Lys27 (H3K27). We show here that these events are causally related and that the MSMB gene, which encodes PSP94, is trimethylated on H3K27 in androgen-refractory, but not in androgensensitive prostate cancer cells. Chromatin immunoprecipitation experiments confirmed an association of EZH2 with the MSMB gene. The RNAi-mediated knockdown of EZH2 resulted in a loss of H3K27 trimethylation and an increased expression of the MSMB gene. Conversely, the overexpression of EZH2 was associated with a decreased expression of the MSMB gene. We also demonstrate that MSMB is additionally repressed in androgen-refractory prostate cancer cells by the hypoacetylation of histone H3K9 and the hypermethylation of a CpG island in the promoter region. Our data disclose a hitherto unexplored link between the putative oncogene EZH2 and the tumor suppressor PSP94, and show that MSMB is silenced by EZH2 in advanced prostate cancer cells.

Multifaceted role of EZH2 in breast and prostate tumorigenesis

“…104 Earlier studies have shown only few candidate genes to be involved in prostate cancer, such as deletion or mutation in PTEN, p53, Nkx3.1, overexpression of oncogenes such as AR and GSTP1 promoter hypermethylation ( Table 1). [105][106][107][108][109][110] But after the advent of high throughput technologies and the completion and T47-D cells. Furthermore, activation of reporter constructs was not observed in ER-negative MDA-MB-231 cells.…”

Growth inhibition properties of the putative prostate cancer biomarkers PSP94 and CRISP-3

“…9 The MSMB gene is (epi)genetically silenced in PCa. [10][11][12][13] Recently, genome-wide association studies identified a C/T single nucleotide polymorphism rs10993994 in the promoter region of the MSMB gene that correlated with a significantly increased risk of developing PCa. 10,11 The 'TT' genotype, comprising two risk alleles, was associated with a lower expression of the MSMB gene and a severely decreased binding of the transcription factor CREB (cyclic AMP response element-binding protein), which was explained by changes of the CREB-binding site.…”

“…12 In addition, the expression of MSMB is downregulated in PCa by methylation of CpG islands as well as by Polycomb-regulated histone modifications, which are both known to silence genes by making them less accessible to transcription factors. 13 It is not yet known whether the CRISP-3 gene is also (epi)genetically misregulated in PCa.…”

Pathogenetic Influences of Human Herpesvirus 8 (HHV-8) in Prostate Cancer Progression

“…This finding is significant as it has been shown that the level of EZH2 expression in tumor specimens directly correlates with worsening prognosis and is most strongly expressed in metastatic and androgen-independent cases (139,140). Additionally, it has been shown that EZH2 epigenetically inhibits the expression of two critical tumor-suppressor proteins, microseminoprotein-beta (MSMB) and DOC-2/DAB2 interactive protein (DAB2IP) (141)(142)(143). MSMB has recently received attention for its potential as a prostate cancer biomarker (rev in 144), while DAB2IP is a Ras GTPase-activating protein that regulates intracellular signal transduction and inhibits prostate cancer cell growth (143,145).…”