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-kappaB and AP-1 signaling and downregulated the expression of multiple oncogenes including MYC, MITF, HMGA2, and CDK6, as well as the NF-kappaB 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.
Highlights
Zinc finger transcription factors are involved broadly in development and tumorigenesis
We found that ZNF382, a Krüppel-associated box (KRAB)-Zinc finger protein (ZFP) we identified previously, is frequently downregulated by promoter
We further found that ectopic expression of ZNF382 in silenced carcinoma cells dramatically inhibits their colony formation by inhibiting cell proliferation and inducing apoptosis
Summary
Zinc finger transcription factors are involved broadly in development and tumorigenesis. We report that the little studied zinc finger transcription factor ZNF382 functions as a tumor suppressor in multiple carcinomas. Ectopic expression of ZNF382 in silenced tumor cells significantly inhibited their clonogenicity and proliferation and induced apoptosis. Our data show that ZNF382 is a functional tumor suppressor frequently methylated in multiple carcinomas. Cancer is caused by aberrant gene regulation, including inactivation of negative regulators of cell proliferation [including tumor suppressor genes (TSG)] and activation of positive regulators Zinc finger protein (ZFP) is the largest family of transcriptional factors with their zinc fingers binding to promoters to activate or repress gene expression [5]. KRAB-ZFPs bind to specific DNA sequences and recruit KRAB-associated protein 1(KAP1), which forms heterochromatin with HP1, SETDB1, and histone deacetylase (HDAC) inhibitor to silence target gene expression [7]. The active form of KRAB-ZFPs is required to initiate heterochromatin formation; irregular KRAB-ZFPs result in failed formation of heterochromatin and uncontrollable gene expression leading to tumorigenesis
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