title: Fhit and Wwox loss-associated genome instability: A genome caretaker one-two punch.
abstract: Expression of Fhit and Wwox protein is frequently lost or reduced in many human cancers. In this report, we provide data that further characterizes the molecular consequences of Fhit loss in the initiation of DNA double-strand breaks (DSBs), and of Wwox loss in altered repair of DSBs. We show that loss of Fhit initiates mild genome instability in early passage mouse kidney cells, confirming that DNA damage associated with Fhit-deficiency is not limited to cancer cells. We also demonstrate that the cause of Fhit-deficient DSBs: thymidine deficiency-induced replication stress, can be resolved with thymidine supplementation in early passage mouse kidney cells before extensive genome instability occurs. As for consequences of Wwox loss in cancer, we show in a small panel of breast cancer cells and mouse embryonic fibroblasts that Wwox expression predicts response to radiation and mitomycin C, all agents that cause DSBs. In addition, loss of Wwox significantly reduced progression free survival in a cohort of ovarian cancer patients treated with platin-based chemotherapies. Finally, stratification of a cohort of squamous lung cancers by Fhit expression reveals that Wwox expression is significantly reduced in the low Fhit-expressing group, suggesting that loss of Fhit is quickly succeeded by loss of Wwox. We propose that Fhit and Wwox loss work synergistically in cancer progression and that DNA damage caused by Fhit could be targeted early in cancer initiation for prevention, while DNA damage caused by Wwox loss could be targeted later in cancer progression, particularly in cancers that develop resistance to genotoxic therapies.
authors: Department of Cancer Biology and Genetics, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors: Morgan S
authors: MS
authors: Schrock
authors: Department of Cancer Biology and Genetics, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors: Jenna R
authors: JR
authors: Karras
authors: Department of Cancer Biology and Genetics, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors: Matthew J
authors: MJ
authors: Guggenbiller
authors: Department of Cancer Biology and Genetics, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors: Teresa
authors: T
authors: Druck
authors: Department of Cancer Biology and Genetics, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors: Bahadir
authors: B
authors: Batar
authors: Department of Cancer Biology and Genetics, The Ohio State University Wexner Medical Center, Columbus, OH, USA. Electronic address: kay.huebner@osumc.edu.
authors: Kay
authors: K
authors: Huebner
mesh_terms: D017766:Acid Anhydride Hydrolases / Q000172:deficiency / Q000235:genetics*; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D042822:Genomic Instability; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D051379:Mice; D009363:Neoplasm Proteins / Q000172:deficiency / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D015398:Signal Transduction; D016019:Survival Analysis; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics*; D000074584:WW Domain-Containing Oxidoreductase / Q000172:deficiency / Q000235:genetics*; D000099170:Bis(5'-adenosyl)triphosphatase
chemical_list: D017766:Acid Anhydride Hydrolases; D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D025521:Tumor Suppressor Proteins; D000074584:WW Domain-Containing Oxidoreductase; D000099170:Bis(5'-adenosyl)triphosphatase; C486071:WWOX protein, human
keywords: Chromosome fragile site; DNA double-strand breaks; Fhit; Genome caretaker; Wwox