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Inhibition of Gli1 Results in Altered C-Jun Activation, Inhibition of Cisplatin-Induced Upregulation of ERCC1, XPD and XRCC1, An

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Inhibition of Gli1 Results in Altered C-Jun Activation, Inhibition of Cisplatin-Induced Upregulation of ERCC1, XPD and XRCC1, An Oncogene (2012) 31, 4718 --4724 & 2012 Macmillan Publishers Limited All rights reserved 0950-9232/12 www.nature.com/onc ORIGINAL ARTICLE Inhibition of Gli1 results in altered c-Jun activation, inhibition of cisplatin-induced upregulation of ERCC1, XPD and XRCC1, and inhibition of platinum--DNA adduct repair K Kudo, E Gavin, S Das, L Amable, LA Shevde and E Reed The transcription of ERCC1 and other nucleotide excision repair (NER) genes is strongly influenced by c-jun. C-jun is transcriptionally regulated by Gli proteins of the Hedgehog pathway. We therefore studied the possible relationships between Gli1, c-jun, and the upregulation of ERCC1, XPD and XRCC1 in cisplatin-resistant human ovarian cancer cells. We studied the paired human ovarian cancer cell lines A2780 and A2780-CP70. We used a shRNA construct that specifically degrades Gli1 message. Genes we assessed for mRNA and/or protein levels included: c-jun, ERCC1, XPD, XRCC1, Gli1, Gli2, SHH, IHH, GAPDH and a-tubulin. Platinum--DNA adduct repair was assessed by atomic absorbance spectrometry with Zeeman background correction. Use of the anti-Gli1 shRNA in cisplatin-resistant cells resulted in a block of the cell’s ability to upregulate genes in response to cisplatin treatment, including: c-jun, ERCC1, XPD and XRCC1. This block in upregulation of c-jun was concurrent with a change in the phosphorylation pattern of the c-jun protein, shifting that pattern from a Ser63/73 dominant pattern, to a Thr91/93 dominant pattern. A2780-CP70 cells were treated at their cisplatin IC50, and DNA repair was assessed after pretreatment with anti-Gli1 shRNA or scrambled shRNA control. Control cells repaired 78% of platinum--DNA adducts at 12 h, compared with 33% repair in cells pretreated with anti-Gli1 shRNA resulting in a 2.4-fold difference. Pretreatment of A2780- CP70 cells with anti-Gli1 shRNA resulted in supra-additive cell killing with cisplatin; shifting the cisplatin IC50 (half maximal inhibitory concentration) from 30 mM to 5 mM. Pretreatment of these cells with cyclopamine did not shift the cisplatin IC50. We conclude that the transcriptional protein Gli1 is important in the upregulation of these three DNA repair genes in human ovarian cancer cells, and that Gli1 strongly influences platinum--DNA adduct repair, and cellular sensitivity to cisplatin. This Gli1 role has c-jun as an intermediate in the pathway. In all, inhibition of Gli1 by a specific shRNA inhibits the upregulation of c-jun Ser63/73, and also inhibits the upregulation of three genes essential to NER (ERCC1, XPD) and base excision repair (XRCC1). Oncogene (2012) 31, 4718--4724; doi:10.1038/onc.2011.610; published online 23 January 2012 Keywords: Gli1; ERCC1; XPD; XRCC1; cisplatin; ovarian cancer INTRODUCTION ERCC1 is necessary for the repair of platinum--DNA damage after Platinum-based anticancer agents are among the most widely an acute exposure to cisplatin.8--10 used agents in clinical oncology.1,2 Nucleotide excision repair ERCC1 is inducible in human cells.8 In human ovarian cancer (NER) is the pathway through which platinum--DNA damage is cells, ERCC1 is upregulated after a 1-h treatment with cisplatin. repaired; and, ERCC1 is a useful biomarker for the NER process in However, a series of events precede the upregulation of ERCC1.8,11 human cells.3--5 Understanding the molecular and pharmacologi- After a 1-h cisplatin IC50 (half maximal inhibitory concentration) cal control of NER may allow for a more complete understanding dose, A2780-CP70 human ovarian cancer cells upregulate the of the modes of cellular and clinical resistance to this class of mRNA and protein of c-jun and c-fos. The peak in mRNA levels agents. In addition, such information may contribute to the occurs at 1--2 h. C-Jun protein is then upregulated, and peaks at development of non-platinum agents that damage DNA and/or 3--5 h after cisplatin. C-Jun protein has to be phosphorylated to be modulate DNA repair. activated. C-Jun phosphorylation is greatly enhanced at 1 h after More than 30 genes are involved in the NER process, which cisplatin treatment, and peaks at 15-fold over baseline 3--5 h after goes from DNA damage recognition, through incision into the cisplatin treatment. C-jun phosphorylation at sites Ser63/73 is DNA strand at sites flanking the DNA damage, through the necessary to activate AP1. AP1 activation leads to increased helicase functions of XPB and XPD, through damage removal, and transcription of ERCC1. through gap-filling and ligation.6,7 DNA damage excision is rate Laner-Plamberger et al.12 reported their findings of the limiting to the process. In DNA damage excision, the last sub-step molecular interface between Gli and c-jun in immortalized is the 50 incision into the DNA strand, relative to the site of keratinocytes. They report that c-jun has five potential Gli binding covalent damage. This 50 incision occurs after the 30 incision, and sites in the promoter of the c-jun gene. Further, there are two after the 30-450 and 50-430 helicase functions of XPB and XPD. c-jun binding sites in the promoter of the c-jun gene. The five Gli The 50 incision is executed by the ERCC1--XPF heterodimer. binding sites are close together, approximately À1000 to À700 in Previous publications from our group show that upregulation of the promoter, relative to the transcription start site. The two c-jun Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA. Correspondence: Dr E Reed, Mitchell Cancer Institute, University of South Alabama, 1660 Springhill Avenue, Mobile, AL 36604, USA. E-mail: [email protected] Received 28 August 2011; revised 18 November 2011; accepted 21 November 2011; published online 23 January 2012 Gli1, c-jun and ERCC1 K Kudo et al 4719 binding sites are approximately 200--300 bases further down- increased slightly. Total c-jun protein level was essentially stream on the promoter, closer to the initiation codon. unchanged, correcting for the GAPDH control. According to their studies, Gli1 upregulates c-jun through one In Figure 1, panels c and d, these two cell lines are compared for specific binding site, but this also requires activated c-jun protein the proteins Shh and Ihh, before and after 24 h of anti-Gli1 shRNA. in their in vitro system.12 Further, Gli2 can upregulate c-jun In the cisplatin-sensitive A2780 cells, levels of Shh and Ihh were through that same specific binding site. When Gli2 and c-jun bind unchanged after 24 h of anti-Gli1 shRNA. In cisplatin-resistant to their respective sites concurrently, there is synergistic A2780-CP70 cells, Shh protein was reduced by a factor of five, upregulation of c-jun. When Gli1 and c-jun bind to the same whereas the Ihh protein level was unchanged. The hedgehog respective sites in the promoter, synergistic upregulation is not ligands are presumed to activate the Hedgehog pathway at the seen. They conclude that Gli1 and Gli2 are positive transcriptional level of the cell membrane by binding to Patched.13 --15 As regulators for c-jun, and that c-jun is a positive transcriptional reduction of Gli1 by shRNA also leads to reduction of Shh in these regulator for itself. In the studies we present, we assess human cells, it suggests that in the development of acquired cisplatin ovarian cancer cells for a possible relationship between Gli1, c-jun resistance, the A2780-CP70 cells developed a feedback loop where and cellular resistance to cisplatin. Gli1 contributes to the cellular production of Shh ligand. Ihh was Our group reported on the relationship between c-jun, AP1 and unaffected. ERCC1.8,11 Laner-Plamberger et al.12 reported on the relationship Data presented in Figure 1 show that when treated with an IC50 between Gli and c-jun. In this report, we investigate the possible dose of anti-Gli1 shRNA, cisplatin-sensitive A2780 human ovarian relationship between Gli, c-jun, ERCC1 and cellular resistance to cancer cells were not affected with respect to Gli1, Gli2, c-jun, Shh cisplatin. or Ihh. However, there were substantive effects that anti-Gli1 shRNA had on cisplatin-resistant A2780-CP70 cells, with respect to Gli1 and Shh. As discussed above, recent reports indicate that the 0 RESULTS c-jun gene has Gli binding sites in its 5 UTR. We next sought to examine more fully, c-jun mRNA and protein We assessed the effects of an IC50 dose of anti-Gli1 shRNA on levels, after an IC50 dose of anti-Gli1 shRNA in cisplatin-resistant cisplatin-sensitive A2780 cells and cisplatin-resistant A2780-CP70 cells. These results are shown in Figure 2. We assessed mRNA cells. The IC50 dose of anti-Gli1 shRNA for these cells is 2 mg/ml levels (panel a) and protein levels (panel b) at 6, 24, 48 and 72 h shRNA per 200 ml well. These results are shown in Figure 1, panels after exposing the cells to an IC50 dose of shRNA. After adjusting a, b, c and d. In panels a and b, the two cell lines are compared for for controls, there was neither an increase in expression at 24 h for the effects on the protein levels of Gli1, Gli2 and c-jun. GAPDH mRNA nor for protein. Also, there was minimal increase in protein is used as the control. In cisplatin-sensitive A2780 cells, expression of mRNA and of protein at 48 and 72 h. there was no apparent effect on Gli1 or Gli2 protein levels. C-jun When A2780-CP70 cells are treated with an IC50 dose of protein may have increased slightly under these conditions.
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