KRAB zinc finger protein ZNF382 is a proapoptotic tumor suppressor that represses multiple oncogenes and is commonly silenced in multiple carcinomas.
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.
Cheng
Yingduan
Y
Department of Clinical Oncology, State Key Laboratory in Oncology in South China/Cancer Epigenetics Laboratory, Sir YK Pao Center for Cancer, Hong Kong Cancer Institute, Chinese University of Hong Kong, Shatin, Hong Kong.
Geng
Hua
H
Cheng
Suk Hang
SH
Liang
Pei
P
Bai
Yan
Y
Li
Jisheng
J
Srivastava
Gopesh
G
Ng
Margaret H L
MH
Fukagawa
Tatsuo
T
Wu
Xiushan
X
Chan
Anthony T C
AT
Tao
Qian
Q
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D019556:COS Cells; D048708:Cell Growth Processes / Q000235:genetics; D002522:Chlorocebus aethiops; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D055786:Gene Knockout Techniques; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D045325:HCT116 Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics; D051798:Inhibitor of Differentiation Protein 1 / Q000235:genetics; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009378:Neoplasms, Multiple Primary / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic; D050796:STAT3 Transcription Factor / Q000235:genetics; D050799:STAT5 Transcription Factor / Q000235:genetics; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*
D004268:DNA-Binding Proteins; C497453:ID1 protein, human; D051798:Inhibitor of Differentiation Protein 1; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050799:STAT5 Transcription Factor; C494095:STAT5B protein, human; D018808:Transcription Factor AP-1; D014157:Transcription Factors; C116326:ZNF382 protein, human; D051550:I-kappa B Kinase; C496565:IKBKE protein, human