Depletion of the cisplatin targeted HMGB-box factor UBF selectively induces p53-independent apoptotic death in transformed cells

// Nourdine Hamdane 1, 2, 3 , Chelsea Herdman 1, 2 , Jean-Clement Mars 1, 2 , Victor Stefanovsky 1 , Michel G. Tremblay 1 , Tom Moss 1, 2 1 Laboratory of Growth and Development, St-Patrick Research Group in Basic Oncology, Cancer Division of the Quebec University Hospital Research Centre, Québec, QC, Canada 2 Department of Molecular Biology, Medical Biochemistry and Pathology, Faculty of Medicine, Laval University, Québec, QC, Canada 3 Present address: Inserm, U1110, Institute of Viral and Liver Diseases, Strasbourg, France Correspondence to: Tom Moss, e-mail: Tom.Moss@crhdq.ulaval.ca Keywords: Upstream binding factor (UBF/UBTF), ribosome biogenesis, oncogenic stress, apoptosis, cisplatin Received: January 23, 2015      Accepted: July 27, 2015      Published: August 07, 2015 ABSTRACT Cisplatin-DNA adducts act as strong decoys for the Upstream Binding Factor UBF (UBTF) and have been shown to inhibit transcription of the ribosomal RNA genes by RNA polymerase I. However, it is unclear if this plays a significant role in the chemotherapeutic activity of cis- or carboplatin. We find that cisplatin in fact induces a very rapid displacement of UBF from the ribosomal RNA genes and strong inhibition of ribosomal RNA synthesis, consistent with this being an important factor in its cytotoxicity. Using conditional gene deletion, we recently showed that UBF is an essential factor for transcription of the ribosomal RNA genes and for ribosome biogenesis. We now show that loss of UBF arrests cell proliferation and induces fully penetrant, rapid and synchronous apoptosis, as well as nuclear disruption and cell death, specifically in cells subjected to oncogenic stress. Apoptosis is not affected by homozygous deletion of the p53 gene and occurs equally in cells transformed by SV40 T antigens, by Myc or by a combination of Ras & Myc oncogenes. The data strongly argue that inhibition of UBF function is a major factor in the cytotoxicity of cisplatin. Hence, drug targeting of UBF may be a preferable approach to the use of the highly toxic platins in cancer therapy.