The Krab-Containing Zinc Finger Protein Znf545 Is A Functional Tumor Suppressor Exerting Proapoptotic And Antiproliferation Abilities With Frequent Epigenetic Inactivation In Multiple Carcinomas

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Epigenetic silencing of tumor suppressor gene is frequently involved in tumor development. Some zinc finger proteins (ZFPs) involved in tumorigenesis are down-regulated through CpG methylation in multiple carcinomas. Here, through genome wide-screening, we identified a novel KRAB domain-containing zinc finger protein (KRAB-ZFP), ZNF545, downregulated in multiple tumor cell lines including nasopharyngeal, esophageal, colon, stomach, liver, kidney, breast, cervix, and prostate carcinomas, in contrast to its broad expression in normal tissues. The promoter of ZNF545 contains a typical CpG island and is frequently methylated in multiple carcinoma cell lines. Transcriptional silencing of ZNF545 could be reversed by pharmacologic demethylation or genetic demethylation, indicating a direct epigenetic silencing mechanism. ZNF545 was also frequently methylated in primary tumors of NPC and ESCC, but less frequently in normal epithelial tissues and paired surgical marginal normal tissues. ZNF545 was found to be a transcriptional repressor when fused to Gal4-binding domain, as determined by the luciferase assay. Ectopic expression of ZNF545 in silenced cancer cell lines significantly inhibited their colony formation, proliferation and induced apoptosis, indicating that ZNF545 can function as a tumor suppressor. ZNF545 also can inhibit the activity of NF-KappaB and AP-1, which play an important role in tumorigenesis. We further found that ZNF545 was located in the nucleus and sequestered in the nucleolus in some cells. ZNF545 could co-localize with KAP1 and heterochromatin protein, so we proposed that ZNF545 could inhibit tumorigenesis, at least partially through downregulating the transcription of target genes, or regulating nucleolus function such as ribosome biogenesis. The tumor specific-silencing of ZNF545 could serve as an epigenetic biomarker for common cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 197.