title: E3 Ligase cIAP2 Mediates Downregulation of MRE11 and Radiosensitization in Response to HDAC Inhibition in Bladder Cancer.
abstract: The MRE11/RAD50/NBS1 (MRN) complex mediates DNA repair pathways, including double-strand breaks induced by radiotherapy. Meiotic recombination 11 homolog (MRE11) is downregulated by histone deacetylase inhibition (HDACi), resulting in reduced levels of DNA repair in bladder cancer cells and radiosensitization. In this study, we show that the mechanism of this downregulation is posttranslational and identify a C-terminally truncated MRE11, which is formed after HDAC inhibition as full-length MRE11 is downregulated. Truncated MRE11 was stabilized by proteasome inhibition, exhibited a decreased half-life after treatment with panobinostat, and therefore represents a newly identified intermediate induced and degraded in response to HDAC inhibition. The E3 ligase cellular inhibitor of apoptosis protein 2 (cIAP2) was upregulated in response to HDAC inhibition and was validated as a new MRE11 binding partner whose upregulation had similar effects to HDAC inhibition. cIAP2 overexpression resulted in downregulation and altered ubiquitination patterns of MRE11 and mediated radiosensitization in response to HDAC inhibition. These results highlight cIAP2 as a player in the DNA damage response as a posttranscriptional regulator of MRE11 and identify cIAP2 as a potential target for biomarker discovery or chemoradiation strategies in bladder cancer.Cancer Res; 77(11); 3027-39. ©2017 AACR.
authors.affiliation: CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, United Kingdom. anne.kiltie@oncology.ox.ac.uk judith.nicholson@oncology.ox.ac.uk.
authors.forename: Judith
authors.initials: J
authors.lastname: Nicholson
authors.affiliation: CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, United Kingdom.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Jevons
authors.affiliation: CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, United Kingdom.
authors.forename: Blaz
authors.initials: B
authors.lastname: Groselj
authors.affiliation: CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, United Kingdom.
authors.forename: Sophie
authors.initials: S
authors.lastname: Ellermann
authors.affiliation: TDI Mass Spectrometry Laboratory, Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Konietzny
authors.affiliation: CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, United Kingdom.
authors.forename: Martin
authors.initials: M
authors.lastname: Kerr
authors.affiliation: TDI Mass Spectrometry Laboratory, Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Benedikt M
authors.initials: BM
authors.lastname: Kessler
authors.affiliation: CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, United Kingdom. anne.kiltie@oncology.ox.ac.uk judith.nicholson@oncology.ox.ac.uk.
authors.forename: Anne E
authors.initials: AE
authors.lastname: Kiltie
mesh_terms: D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D015536:Down-Regulation; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use*; D006801:Humans; D000076228:MRE11 Homologue Protein; D011836:Radiation Tolerance; D014162:Transfection; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D001749:Urinary Bladder Neoplasms / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D056572:Histone Deacetylase Inhibitors; C121766:MRE11 protein, human; D044767:Ubiquitin-Protein Ligases; D000076228:MRE11 Homologue Protein