A Novel 19q13 Nucleolar Zinc Finger Protein Suppresses Tumor Cell Growth through Inhibiting Ribosome Biogenesis and Inducing Apoptosis but Is Frequently Silenced in Multiple Carcinomas

Abstract

Epigenetic disruption of tumor suppressor genes is frequently involved in tumorigenesis. We identified a novel 19q13 KRAB domain-containing zinc finger protein, ZNF545/ZFP82, broadly expressed in normal tissues but downregulated in multiple tumor cell lines. The ZNF545 promoter contains a CpG island, which is frequently methylated in cell lines. The transcriptional silencing of ZNF545 could be reversed by pharmacologic or genetic demethylation, indicating direct epigenetic silencing. ZNF545 was also frequently methylated in multiple primary tumors of nasopharyngeal, esophageal, lung, gastric, colon, and breast, but rarely in normal epithelial tissues and paired normal tissues. ZNF545 is located in the nucleus and mainly sequestered in nucleoli, functioning as a repressor. ZNF545 is able to repress NF-kB and AP-1 signaling pathways, whereas ectopic expression of ZNF545 in silenced tumor cells significantly inhibited their growth and induced apoptosis. Functional studies showed that ZNF545 was involved in ribosome biogenesis through inhibiting the activity of rDNA promoter and decreasing cellular protein translation efficiency. Thus, we identified ZNF545 as a novel tumor suppressor inducing tumor cell apoptosis, repressing ribosome biogenesis and target gene transcription. The tumor-specific methylation of ZNF545 could be an epigenetic biomarker for cancer diagnosis. Mol Cancer Res; 10(7); 925-36. Ó2012 AACR.

Zinc-Finger Protein 545 Inhibits Cell Proliferation as a Tumor Suppressor through Inducing Apoptosis and is Disrupted by Promoter Methylation in Breast Cancer

“…ZNF545 is reportedly a functional tumor suppressor in multiple cancers and is silenced by promoter methylation by our group [14], [26]. This is the first study to elucidate the direct relationship between ZNF545 and breast cancer.…”

“…Our previously studies have demonstrated that ZNF545 is frequently silenced by promoter methylation in multiple carcinomas including esophageal, nasopharyngeal, gastric, colorectal, and breast cancer [14], [26], [28]. To identify the relationship between the clinicopathological features and methylation status of ZNF545 in breast tumorigenesis, and to develop biomarkers for breast cancer detection and prognosis, ZNF545 methylation was examined in 29% of primary breast tumor tissues, but not in normal tissues, consistent with our previous study [14]. No significant associations were found between clinicopathological features and methylation status, although this needs to be further confirmed by studies using more samples.…”

“…Both NF-κB and AP-1 signaling pathways play important roles in the regulation of cell proliferation, survival, apoptosis, and malignant transformation [31], [32]. Previous reports revealed that the ectopic expression of ZNF545 suppresses AP-1 and NF-κB signaling, and inhibits the expression of multiple oncogenes in tumor cells [14]. We found that ZNF545 increased the transcription of c-Jun/AP1, BAX, p53 and Caspase 3, and then confirmed by Western blot, thus may serve as a transcriptional repressor in Luminal A subtype breast cancer.…”

“…Several KRAB-ZFPs, such as ZNF382 and ZNF569, have been identified as tumor suppressors [9], [10], whereas others, such as ZNF217, GLI1, and ZNF147, serve as app:modword:serve asoncogenic proteins [7], [11], [12], [13]. However, the roles for most KRAB-ZFP family members in carcinogenesis remain ambiguous including breast cancer [14].…”

OSR1 is a novel epigenetic silenced tumor suppressor regulating invasion and proliferation in renal cell carcinoma

“…Currently, it is well accepted that epigenetic alterations even precede genetic changes during tumorigenesis [3]. An increasing number of epigenetic silenced tumor suppressor genes (TSGs) were identified in multiple cancers [4–8], which exert antitumor effects but silenced by promoter methylation in tumor specific manner.…”