Thap11 Genetic Inhibition Of Cell Proliferation And Its Mechanism

Recently, the THAP proteins characterized by the presence of an evolutionary conserved protein motif have been described. Many findings suggest that THAP proteins may function as sequence-specific DNA-binding factors with roles in cell proliferation, apoptosis, chromatin modification, and transcriptional regulation.THAP11 is the last member of this human family. Here, we identified THAP11 as a ubiquitously expressed gene and frequently down-expressed in several human tumor tissues. We constructed stable HEK293 cell lines capable of expressing THAPl 1 from ecdysone-responsive promoter, and demonstrated that the cell growth was inhibited when THAP11 was induced in these cells. Furthermore we found that expression of THAP11 led to a reduction in transcription of c-myc, and down-regulation of Nucleolin and Ornithine decarboxylase (ODC), the target genes of c-myc, involved in THAP11-mediated growth inhibition. To clarify the mechanism of THAP11 down-regulation of c-myc promoter activity, we constructed a serious of delete mutation of c-myc promoter reporter, and located the region that THAP11 acted on c-myc promoter. And then, a direct physical interaction between THAP11 and the c-myc promoter was detected both in vitro with EMSA and in vivo with ChIP. Moreover, We provided evidence that over-expression of c-myc significantly rescued cells from THAP11-mediated cell growth suppression, suggested that THAPl 1-mediated growth inhibition partially through down-regulation of c-myc expression.The gene encoding THAP11 maps to a region of human chromosome 16q22.1, that is often deleted in human malignancies. Considering THAP11 down-expression in several kinds of human tumor tissues, we concluded that THAP11 function as a DNA-binding protein with roles in growth ,transcriptional regulation and may as a potential candidate for tumor suppressor. it is the first identification of endogenous targeting gene of a human THAP family protein in our report.