title: Harnessing the p53-PUMA axis to overcome DNA damage resistance in renal cell carcinoma.
abstract: Resistance to DNA damage-induced apoptosis is a hallmark of cancer and a major cause of treatment failure and lethal disease outcome. A tumor entity that is largely resistant to DNA-damaging therapies including chemo- or radiotherapy is renal cell carcinoma (RCC). This study was designed to explore the underlying molecular mechanisms of DNA damage resistance in RCC to develop strategies to resensitize tumor cells to DNA damage-induced apoptosis. Here, we show that apoptosis-resistant RCC cells have a disconnect between activation of p53 and upregulation of the downstream proapoptotic protein p53 upregulated modulator of apoptosis (PUMA). We demonstrate that this disconnect is not caused by gene-specific repression through CCCTC-binding factor (CTCF) but instead by aberrant chromatin compaction. Treatment with an HDAC inhibitor was found to effectively reactivate PUMA expression on the mRNA and protein level and to revert resistance to DNA damage-induced cell death. Ectopic expression of PUMA was found to resensitize a panel of RCC cell lines to four different DNA-damaging agents tested. Remarkably, all RCC cell lines analyzed were wild-type for p53, and a knockdown was likewise able to sensitize RCC cells to acute genotoxic stress. Taken together, our results indicate that DNA damage resistance in RCC is reversible, involves the p53-PUMA axis, and is potentially targetable to improve the oncological outcomes of RCC patients.
authors.affiliation: Molecular Urooncology, Department of Urology, University of Heidelberg School of Medicine, Im Neuenheimer Feld 517, D-69120 Heidelberg, Germany.
authors.forename: Xiaoguang
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Molecular Urooncology, Department of Urology, University of Heidelberg School of Medicine, Im Neuenheimer Feld 517, D-69120 Heidelberg, Germany.
authors.forename: Yanis
authors.initials: Y
authors.lastname: Tolstov
authors.affiliation: Molecular Urooncology, Department of Urology, University of Heidelberg School of Medicine, Im Neuenheimer Feld 517, D-69120 Heidelberg, Germany.
authors.forename: Aysenur
authors.initials: A
authors.lastname: Arslan
authors.affiliation: Department of Pathology, University of Heidelberg School of Medicine, Im Neuenheimer Feld 224, D-69120 Heidelberg, Germany.
authors.forename: Wilfried
authors.initials: W
authors.lastname: Roth
authors.affiliation: National Center for Tumor Diseases (NCT), Medical Oncology, Im Neuenheimer Feld 460, D-69120 Heidelberg, Germany; Center for Kidney Tumors, National Center for Tumor Disease and University of Heidelberg School of Medicine, Im Neuenheimer Feld 460, D-69120 Heidelberg, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Grüllich
authors.affiliation: Center for Kidney Tumors, National Center for Tumor Disease and University of Heidelberg School of Medicine, Im Neuenheimer Feld 460, D-69120 Heidelberg, Germany; Department of Urology, University of Heidelberg School of Medicine, Im Neuenheimer Feld 110, D-69120 Heidelberg, Germany.
authors.forename: Sascha
authors.initials: S
authors.lastname: Pahernik
authors.affiliation: Center for Kidney Tumors, National Center for Tumor Disease and University of Heidelberg School of Medicine, Im Neuenheimer Feld 460, D-69120 Heidelberg, Germany; Department of Urology, University of Heidelberg School of Medicine, Im Neuenheimer Feld 110, D-69120 Heidelberg, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Hohenfellner
authors.affiliation: Molecular Urooncology, Department of Urology, University of Heidelberg School of Medicine, Im Neuenheimer Feld 517, D-69120 Heidelberg, Germany; Center for Kidney Tumors, National Center for Tumor Disease and University of Heidelberg School of Medicine, Im Neuenheimer Feld 460, D-69120 Heidelberg, Germany; Department of Urology, University of Heidelberg School of Medicine, Im Neuenheimer Feld 110, D-69120 Heidelberg, Germany. Electronic address: stefan.duensing@med.uni-heidelberg.de.
authors.forename: Stefan
authors.initials: S
authors.lastname: Duensing
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000473:pathology; D002470:Cell Survival; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000235:genetics; D004351:Drug Resistance / Q000235:genetics*; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000473:pathology; D008856:Microscopy, Fluorescence; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; D004273:DNA, Neoplasm; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53