RIZ1 is epigenetically inactivated by promoter hypermethylation in thyroid carcinoma

Abstract

BACKGROUND. Allelotype studies have suggested that chromosome 1p is frequently lost in thyroid cancers, thus suggesting that there is an important tumor suppressor at this location. RIZ1 (PRDM2), located on 1p36, is a recently described tumor suppressor gene and is a member of the protein methyltransferase superfamily. RIZ1 expression is lost in a variety of tumors, primarily by means of epigenetic mechanisms that involve promoter hypermethylation.METHODS. RIZ1 expression was examined in a panel of thyroid tumor cell lines and primary thyroid tissues (14 normal, 19 benign, and 31 cancerous) by using real-time polymerase chain reaction (PCR). Methylation status of the RIZ1 promoter was studied using bisulfite sequencing and methylation-specific PCR. RESULTS.The authors demonstrated that RIZ1 expression is lost in thyroid tumor cell lines and is also significantly reduced in thyroid carcinomas, when compared with normal thyroid tissues (P < .0001) and benign tumors (P ¼ .0003). The current study results also showed that loss of RIZ1 is mediated by aberrant cytosine methylation of the RIZ1 promoter. One hundred percent of carcinomas were methylated, compared with 33% of normal thyroid tissues (P ¼ .001). RIZ1 mRNA expression was significantly higher (P ¼ .02) in unmethylated (1.22 6 1.2, mean 6 standard deviation [SD]), compared with methylated tissues (0.37 6 0.42, mean 6 SD). Last, treatment with a DNA methyltransferase inhibitor led to reactivation of RIZ1 expression in cell lines that had negligible RIZ1 expression at baseline. CONCLUSIONS.The current study suggested an important role for RIZ1 expression in thyroid tumorigenesis and identified a potential novel therapeutic target for tumors unresponsive to other therapies.

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).…”

Regulation of 14-3-3σ expression in human thyroid carcinoma is epigenetically regulated by aberrant cytosine methylation

“…A review of the literature demonstrates that KAK-1 appears to be morphologically similar to other thyroid carcinoma-derived cell lines such as KAT-4 and KAT-10 [28]. In addition, it seems to have lost expression of several genes, similar to other thyroid carcinoma cell lines [25,[29][30][31]. In this regard, KAK-1 may behave more like a malignant rather than a benign tumor-derived cell line in culture.…”

“…The duration of drug treatment was selected based on the growth patterns of this cell line and previous studies from our lab using other thyroid cancer cell lines [25].…”

HORMAD2 methylation‐mediated epigenetic regulation of gene expression in thyroid cancer

“…Watson et al11 reported that increased DNA methylation in the HoxA5 promoter region contributed to tumour growth via down‐regulation of HoxA5 expression. Lal et al demonstrated that RIZ1 was epigenetically inactivated by promoter hypermethylation in thyroid carcinoma and identified as a potential novel therapeutic target 12. Thus, aberrant promoter methylation may be an effective way to detect candidate targets for THCA treatment.…”