KRAB Zinc Finger Protein ZNF382 Is a Proapoptotic Tumor Suppressor That Represses Multiple Oncogenes and Is Commonly Silenced in Multiple Carcinomas

Abstract

Zinc finger transcription factors are involved broadly in development and tumorigenesis. Here, we report that the little studied zinc finger transcription factor ZNF382 functions as a tumor suppressor in multiple carcinomas. Although broadly expressed in normal tissues, ZNF382 expression was attenuated in multiple carcinoma cell lines due to promoter CpG methylation. ZNF382 was also frequently methylated in multiple primary tumors (nasopharyngeal, esophageal, colon, gastric, and breast). Ectopic expression of ZNF382 in silenced tumor cells significantly inhibited their clonogenicity and proliferation and induced apoptosis. We further found that ZNF382 inhibited NF-κB and AP-1 signaling and downregulated the expression of multiple oncogenes including MYC, MITF, HMGA2, and CDK6, as well as the NF-κB upstream factors STAT3, STAT5B, ID1, and IKBKE, most likely through heterochromatin silencing. ZNF382 could suppress tumorigenesis through heterochromatin-mediated silencing, as ZNF382 was colocalized and interacted with heterochromatin protein HP1 and further changed the chromatin modifications of ZNF382 target oncogenes. Our data show that ZNF382 is a functional tumor suppressor frequently methylated in multiple carcinomas. Cancer Res; 70(16); 6516-26. ©2010 AACR.

The Metalloprotease ADAMTS8 Displays Antitumor Properties through Antagonizing EGFR–MEK–ERK Signaling and Is Silenced in Carcinomas by CpG Methylation

“…Multiple cell lines of NPC, ESCC, gastric, and CRC, hepatocellular (HCC), lung, breast, RCC, and cervical carcinomas and several immortalized normal epithelial cell lines were used (19,20). Cell lines were obtained either from the American Type Culture Collection or our collaborators.…”

“…20 and 22). Genomic DNA samples of normal nasopharyngeal and gastric tissues, as well as primary tumor tissues of nasopharyngeal carcinoma, gastric cancer, and colorectal carcinoma, have been described previously (19,(23)(24)(25). Clinical information was available for the majority of gastric cancer samples.…”

“…Cells grown on coverslips were stained by immunofluorescence as described previously (19,20). In brief, HONE1 or KYSE150 cells were transfected with pcDNA3.1 (þ)-ADAMTS8-Flag or pEGFP-N1-ADAMTS8 plasmid.…”

“…Reporter activity of the serum response element (SRE)-luc, AP-1 plasmids (Stratagene) was determined in HONE1 and KYSE150 cells as described previously (19,28). Subconfluent cells in 24-well plates were transiently cotransfected with pSRE-luc, pcDNA3.1(þ)-ADAMTS8-Flag and pRL-SV40.…”

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

“…Some ZFPs function as oncogenic proteins such as ZNF217 and ZNF639 (1,2), whereas others can act as tumor suppressors, such as ZAC, ST18, and ZNF382 (3)(4)(5). ZFPs bind to promoters with their zinc finger domains and activate or repress gene expression through their association proteins (1,6).…”