DNA methylation of the RIZ1 gene is associated with nuclear accumulation of p53 in prostate cancer

Abstract

The retinoblastoma protein-interacting zinc finger gene, RIZ1, is thought to be a tumor suppressor gene. RIZ1 is inactivated by mutation, deletion and DNA methylation in several human cancers. In the present study, the relationship between DNA methylation of RIZ1 and mutation of p53 was investigated in prostate cancer (PCa). In total, 47 cases of node-negative PCa (stages I-III) were analyzed. DNA methylation of the RIZ1 gene was detected in 20 (42.6%) of the 47 PCa tissues by methylation-specific polymerase chain reaction. DNA methylation of the RIZ1 gene was not associated with clinicopathological features. DNA methylation of RIZ1 tended to be present more frequently in PCa specimens with a high Gleason score (16/30, 53.3%) than in those with a low Gleason score (4/17, 23.5%); however, this tendency was not statistically significant (P = 0.0675). Nuclear accumulation of p53 was observed in four (8.5%) of 47 PCa specimens by immunostaining. All four PCa specimens with nuclear accumulation of p53 were stage III disease and showed DNA methylation of RIZ1. However, of the remaining 43 cancers without nuclear accumulation of p53, DNA methylation of RIZ1 was observed in only 16 (37.2%) specimens (P = 0.0272). Of the three PCa cell lines, only the PC3 cell line showed loss of RIZ1 mRNA due to DNA methylation, and this loss was rectified by treatment with a demethylating agent, 5-Aza-2′ ′ ′ ′-deoxycytidine. These results suggest that transcriptional inactivation of RIZ1 by aberrant DNA methylation may contribute to prostate carcinogenesis. Genetic alterations are likely associated with epigenetic alterations in PCa. (Cancer Sci 2007; 98: 32-36) P rostate cancer (PCa) is one of the most common cancers and the second leading cause of cancer death in men in the USA.(1) An understanding of the genetic and epigenetic pathways involved in the pathogenesis of PCa is essential for development of improved diagnostic and treatment modalities. A variety of genetic and epigenetic alterations are associated with PCa. (2,3) Epigenetic changes, such as DNA methylation of CpG islands, are detected commonly in human cancers. Hypermethylation of CpG islands is associated with silencing of many genes, especially defective tumor-related genes, and has been proposed as an alternative way to inactivate tumor-related genes in human cancers.(4,5) Identification of methylated genes may be useful in the diagnosis and treatment of PCa and may provide insight into prostate carcinogenesis. Prior studies have shown that DNA hypermethylation is a crucial mechanism in transcriptional silencing of tumor-related genes in PCa. (6,7) The retinoblastoma protein-interacting zinc finger gene, RIZ1, was isolated with a functional screen for retinoblastoma (Rb)-binding proteins.(8) Domain analysis suggested that RIZ1 is a histone methyltransferase (HMT) specific for the lysine 9 residue of histone H3, an activity known to be linked with transcriptional repression.(9) RIZ1 is considered to be a tumor suppressor gene because it can induce G 2 -M arrest and apo...

Expression of RIZ1 protein (Retinoblastoma‐interacting zinc‐finger protein 1) in prostate cancer epithelial cells changes with cancer grade progression and is modulated in vitro by DHT and E2

“…The disappearance of the PR-domain-containing RIZ1 gene product, which is endowed with tumor suppressive properties, has already been described in many tumors because genetic alterations such as gene deletions or mutations (He et al, 1998;Huang, 1999;Chadwick et al, 2000;Piao et al, 2000;Fang et al, 2001;Sakurada et al, 2001;Steele-Perkins et al, 2001;Poetch et al, 2002;Sasaki et al, 2002;Geli et al, 2005). RIZ gene was found methylated in near 35% of prostate cancer samples (Suzuki et al, 2006;Hasegawa et al, 2007). Increased DNA methylation in prostate cancers with a high Gleason score is in accordance with more frequent gene silencing in these samples (Du et al, 2001).…”

“…Data on the expression and role of RIZ1 in human normal or tumor prostate tissues are very limited. Methylation of the RIZ1 promoter has been described in nearly 35% of prostate cancer tissues, which suggests that epigenetic silencing of this gene may be involved in prostate cancer development (Suzuki et al, 2006;Hasegawa et al, 2007). The RIZ1 protein is also a downstream effector of estrogen action in classical estrogen target tissues.…”

DNA methylation and carcinogenesis of PRDM5 in cervical cancer

“…PRDM1/BLIMP1 was originally identified as a transcript that was rapidly induced during the differentiation of B lymphocytes into immunoglobulin secretory cells; its expression is characteristic of late B and plasma cell lines (Huang 1994;Turner et al 1994), and it is mutated in diffuse large B-cell lymphoma (Pasqualucci et al 2006). PRDM2/RIZ1 has histone methyltransferase activity Huang et al 1998;Du et al 2001), and its aberrant methylation has been reported in various types of cancers (Oshimo et al 2004;Takahashi et al 2004;Hasegawa et al 2007;Lal et al 2006). Both PRDM2 and PRDM1 have growth arrest and proapoptotic activities (He et al 1998;Jiang et al 1999;Jiang and Huang 2001;Lin et al 1997).…”

Suppression of RIZ in biologically unfavourable neuroblastomas

“…Epigenetic inactivation by promoter methylation has been implicated as a common mechanism underlying RIZ1 silencing (20,(26)(27)(28)(29)(30). In view of these findings, and our present observation of frequent suppression of RIZ1 mRNA expression we have quantitatively assessed RIZ1 promoter methylation in the tumor panel and four neuroblastoma cell lines.…”

“…Somatic RIZ mutations have also been reported, such as frameshift mutations at the C terminus in association with microsatellite instability (21,25), and missense mutations at the N-terminal PR domain in various tumors and cancer cell lines (17). Finally, hypermethylation of promoter P1 has been reported in different types of tumors (20,(26)(27)(28)(29)(30).…”