title: Loss of DOK2 induces carboplatin resistance in ovarian cancer via suppression of apoptosis.
abstract: OBJECTIVE
  Ovarian cancers are highly heterogeneous and while chemotherapy is the preferred treatment many patients are intrinsically resistant or quickly develop resistance. Furthermore, all tumors that recur ultimately become resistant. Recent evidence suggests that epigenetic deregulation may be a key factor in the onset and maintenance of chemoresistance. We set out to identify epigenetically silenced genes that affect chemoresistance.
  
  
  METHODS
  The epigenomes of a total of 45 ovarian samples were analyzed to identify epigenetically altered genes that segregate with platinum response, and further filtered with expression data to identify genes that were suppressed. A tissue culture carboplatin resistance screen was utilized to functionally validate this set of candidate platinum resistance genes.
  
  
  RESULTS
  Our screen correctly identified 19 genes that when suppressed altered the chemoresistance of the cells in culture. Of the genes identified in the screen we further characterized one gene, docking protein 2 (DOK2), an adapter protein downstream of tyrosine kinase, to determine if we could elucidate the mechanism by which it increased resistance. The loss of DOK2 decreased the level of apoptosis in response to carboplatin. Furthermore, in cells with reduced DOK2, the level of anoikis was decreased.
  
  
  CONCLUSIONS
  We have developed a screening methodology that analyzes the epigenome and informatically identifies candidate genes followed by in vitro culture screening of the candidate genes. To validate our screening methodology we further characterized one candidate gene, DOK2, and showed that loss of DOK2 induces chemotherapy resistance by decreasing the level of apoptosis in response to treatment.
authors.affiliation: Cold Spring Harbor, Woodbury, NY, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Lum
authors.forename: Michele
authors.initials: M
authors.lastname: Vigliotti
authors.forename: Nilanjana
authors.initials: N
authors.lastname: Banerjee
authors.forename: Noelle
authors.initials: N
authors.lastname: Cutter
authors.forename: Kazimierz O
authors.initials: KO
authors.lastname: Wrzeszczynski
authors.forename: Sohail
authors.initials: S
authors.lastname: Khan
authors.forename: Sitharthan
authors.initials: S
authors.lastname: Kamalakaran
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Levine
authors.forename: Nevenka
authors.initials: N
authors.lastname: Dimitrova
authors.forename: Robert
authors.initials: R
authors.lastname: Lucito
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000502:physiology*; D023102:Anoikis; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D016190:Carboplatin / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019175:DNA Methylation; D019008:Drug Resistance, Neoplasm; D044127:Epigenesis, Genetic; D005260:Female; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010750:Phosphoproteins / Q000235:genetics / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; C115089:DOK2 protein, human; D010750:Phosphoproteins; D016190:Carboplatin
keywords: Apoptosis; Epigenetics; Genomics; Ovarian Cancer; Platinum resistance