Cisplatin is one of the most potent and widely used anti-cancer agents in the treatment of various solid tumors. However, the development of resistance to cisplatin is a major obstacle in clinical treatment. Several mechanisms are thought to be involved in cisplatin resistance, including decreased intracellular drug accumulation, increased levels of cellular thiols, increased nucleotide excision-repair activity and decreased mismatch-repair activity. In general, the molecules responsible for each mechanism are upregulated in cisplatin-resistant cells; this indicates that the transcription factors activated in response to cisplatin might play crucial roles in drug resistance. It is known that the tumor-suppressor proteins p53 and p73, and the oncoprotein c-Myc, which function as transcription factors, influence cellular sensitivity to cisplatin. So far, we have identified several transcription factors involved in cisplatin resistance, including Y-box binding protein-1 (YB-1), CCAAT-binding transcription factor 2 (CTF2), activating transcription factor 4 (ATF4), zinc-finger factor 143 (ZNF143) and mitochondrial transcription factor A (mtTFA). Two of these-YB-1 and ZNF143-lack the high-mobility group (HMG) domain and can bind preferentially to cisplatin-modified DNA in addition to HMG domain proteins or DNA repair proteins, indicating that these transcription factors may also participate in DNA repair. In this review, we summarize the mechanisms of cisplatin resistance and focus on transcription factors involved in the genomic response to cisplatin.
Zinc-finger protein 143 (ZNF143) is a human homolog of Xenopus transcriptional activator staf that is involved in selenocystyl tRNA transcription. We previously showed that ZNF143 expression is induced by treatment with DNA-damaging agents and that it preferentially binds to cisplatin-modified DNA. In this study, the potential function of ZNF143 was investigated. ZNF143 was overexpressed in cisplatin-resistant cells. ZNF143 knockdown in prostate cancer caused increased sensitivity for cisplatin, but not for oxaliplatin, etoposide and vincristine. We also showed that ZNF143 is associated with tumor suppressor gene product p73 but not with p53. p73 could stimulate the binding of ZNF143 to both ZNF143 binding site and cisplatin-modified DNA, and modulate the function of ZNF143. We provide a direct evidence that both Rad51 and flap endonuclease-1 are target genes of ZNF143 and overexpressed in cisplatin-resistant cells. Taken together, these experiments demonstrate that an interplay of ZNF143, p73 and ZNF143 target genes is involved in DNA repair gene expression and cisplatin resistance.
The cell cycle is strictly regulated by numerous mechanisms to ensure cell division. The transcriptional regulation of cell-cyclerelated genes is poorly understood, with the exception of the E2F family that governs the cell cycle. Here, we show that a transcription factor, zinc finger protein 143 (ZNF143), positively regulates many cell-cycle-associated genes and is highly expressed in multiple solid tumors. RNA-interference (RNAi)-mediated knockdown of ZNF143 showed that expression of 152 genes was downregulated in human prostate cancer PC3 cells. Among these ZNF143 targets, 41 genes (27%) were associated with cell cycle and DNA replication including cell division cycle 6 homolog (CDC6), polo-like kinase 1 (PLK1) and minichromosome maintenance complex component (MCM) DNA replication proteins. Furthermore, RNAi of ZNF143 induced apoptosis following G2 ⁄ M cell cycle arrest. Cell growth of 10 lung cancer cell lines was significantly correlated with cellular expression of ZNF143. Our data suggest that ZNF143 might be a master regulator of the cell cycle. Our findings also indicate that ZNF143 is a member of the growing list of non-oncogenes that are promising cancer drug targets. (Cancer Sci 2010; 101: 2538-2545 T ranscriptional regulation of gene expression requires the orchestrated recruitment of transcription factors by sequence-specific DNA binding regulators. Staf was initially identified as the transcriptional activator of the RNA polymerase III-dependent Xenopus tRNA gene.(1) It has recently been shown that its human ortholog zinc finger protein 143 (ZNF143; formerly known as hStaf) is also involved in RNA-polymerase-IIdependent gene transcription.(2,3) The DNA binding domain of ZNF143 is located in the central part of the protein and consists of seven zinc finger domains.(1,4) The ZNF143 DNA binding site is thought to be at least 18 bp long because the protein has seven zinc fingers; by analogy, the well-known zinc finger transcription factor Sp family and members of the KLF family contain three zinc fingers and recognize DNA sequences approximately 6 bp long.(5) Recently, it has been shown by a bioinformatics approach that ZNF143 binding sites are widely distributed in the CpG island-type promoters of the human genome.(6) Functional classification of ZNF143 target genes has revealed that many of the identified genes are important for cell growth: 27% of the genes are categorized as cell cycle ⁄ DNA replication ⁄ DNA repair proteins.We have previously reported that expression of ZNF143 is induced by DNA-damaging agents and is enhanced in cisplatinresistant cell lines.(7) ZNF143 binds preferentially to cisplatinmodified DNA. We also found that ZNF143 binding sites are frequently found in the promoter region of DNA repair genes. Here, we investigated the ZNF143 target genes by RNA interference (RNAi). One hundred and fifty-two genes were downregulated by ZNF143-specific small interfering RNA (siRNA) transfection. Among them, 41 genes are categorized as concerned with cell cycle and DNA replication. ZNF143 wa...
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