Role of ZNF143 in tumor growth through transcriptional regulation of DNA replication and cell‐cycle‐associated genes

Abstract

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...

The combination of strong expression of ZNF143 and high MIB-1 labelling index independently predicts shorter disease-specific survival in lung adenocarcinoma

“…The cell cycle is strictly regulated by various mechanisms to ensure cell division and, thus, the transcriptional regulation of cell-cycle-related genes expression requires the orchestrated recruitment of transcription factors, but it remains to be elucidated. We and others have previously revealed that a transcription factor, zinc finger protein 143 (ZNF143), which is a human homologue of the Xenopus transcriptional activator, Staf, positively regulates many DNA replication and cell-cycle-associated genes (Myslinski et al , 2007; Izumi et al , 2010; Hernández-Negrete et al , 2011). In fact, according to the DNA microarray analysis with ZNF143 -specific small interfering RNA (siRNA) transfection, 41 (27.0%) genes were categorised as concerned with the cell-cycle/DNA replication, such as Aurora kinase B or High-mobility group box 2 , among the <0.4-fold downregulated 152 genes (Izumi et al , 2010).…”

“…We and others have previously revealed that a transcription factor, zinc finger protein 143 (ZNF143), which is a human homologue of the Xenopus transcriptional activator, Staf, positively regulates many DNA replication and cell-cycle-associated genes (Myslinski et al , 2007; Izumi et al , 2010; Hernández-Negrete et al , 2011). In fact, according to the DNA microarray analysis with ZNF143 -specific small interfering RNA (siRNA) transfection, 41 (27.0%) genes were categorised as concerned with the cell-cycle/DNA replication, such as Aurora kinase B or High-mobility group box 2 , among the <0.4-fold downregulated 152 genes (Izumi et al , 2010). For example, ZNF143 plays a central role in regulating the mitochondrial transcriptional initiation and replication of mitochondrial DNA (Gérard et al , 2007).…”

“…Indeed, ZNF143 is a critical regulator of mammalian normal development and embryonic stem cell renewal (Chen et al , 2008; Chia et al , 2010; Halbig et al , 2012). In contrast, it is specifically expressed in multiple solid tumours, including lung cancer, oesophageal and gastric cancer, urothelial carcinoma, or cerebral astrocytoma (Izumi et al , 2010). Various collecting data in our group also demonstrated that cell growth of lung cancer cell lines was significantly correlated with ZNF143 expression, whereas downregulation of ZNF143 strongly induced apoptosis following G2/M cell cycle arrest (Izumi et al , 2010).…”

“…In contrast, it is specifically expressed in multiple solid tumours, including lung cancer, oesophageal and gastric cancer, urothelial carcinoma, or cerebral astrocytoma (Izumi et al , 2010). Various collecting data in our group also demonstrated that cell growth of lung cancer cell lines was significantly correlated with ZNF143 expression, whereas downregulation of ZNF143 strongly induced apoptosis following G2/M cell cycle arrest (Izumi et al , 2010). It is very likely that ZNF143 might not only regulate basic cellular functions at the transcriptional level, but be the parameter of cell proliferative activity, very similar to the widely accepted Ki67 (MIB-1) protein (Burger et al , 1986; Oka et al , 2011), and subsequently be promising targets for lung cancer diagnoses and therapies.…”

The combination of a nuclear HMGB1-positive and HMGB2-negative expression is potentially associated with a shortened survival in patients with pancreatic ductal adenocarcinoma

“…In order to obtain the pcDNA3-hemagglutinin (HA)-HMGB1 or pcDNA3-HA-HMGB2, full-length HMGB1 or HMGB2 complementary DNA (cDNA) was prepared from each GST expression plasmid [26], and the NH 2 -terminal HA-tagged HMGB1 or HMGB2 cDNA was ligated into a pcDNA3 vector (Invitrogen, San Diego, CA, USA) [27,28]. Transient transfection and immunoprecipitation (IP) assays were performed as previously described [27].…”