title: High throughput synthetic lethality screen reveals a tumorigenic role of adenylate cyclase in fumarate hydratase-deficient cancer cells.
abstract: BACKGROUND
  Synthetic lethality is an appealing technique for selectively targeting cancer cells which have acquired molecular changes that distinguish them from normal cells. High-throughput RNAi-based screens have been successfully used to identify synthetic lethal pathways with well-characterized tumor suppressors and oncogenes. The recent identification of metabolic tumor suppressors suggests that the concept of synthetic lethality can be applied to selectively target cancer metabolism as well.
  
  
  RESULTS
  Here, we perform a high-throughput RNAi screen to identify synthetic lethal genes with fumarate hydratase (FH), a metabolic tumor suppressor whose loss-of-function has been associated with hereditary leiomyomatosis and renal cell carcinoma (HLRCC). Our unbiased screen identified synthetic lethality between FH and several genes in heme metabolism, in accordance with recent findings. Furthermore, we identified an enrichment of synthetic lethality with adenylate cyclases. The effects were validated in an embryonic kidney cell line (HEK293T) and in HLRCC-patient derived cells (UOK262) via both genetic and pharmacological inhibition. The reliance on adenylate cyclases in FH-deficient cells is consistent with increased cyclic-AMP levels, which may act to regulate cellular energy metabolism.
  
  
  CONCLUSIONS
  The identified synthetic lethality of FH with adenylate cyclases suggests a new potential target for treating HLRCC patients.
authors.forename: Michael
authors.initials: M
authors.lastname: Boettcher
authors.forename: Andrew
authors.initials: A
authors.lastname: Lawson
authors.forename: Viola
authors.initials: V
authors.lastname: Ladenburger
authors.forename: Johannes
authors.initials: J
authors.lastname: Fredebohm
authors.forename: Jonas
authors.initials: J
authors.lastname: Wolf
authors.forename: Jörg D
authors.initials: JD
authors.lastname: Hoheisel
authors.affiliation: MRC Cancer Unit, Cambridge Biomedical Campus, University of Cambridge, Hutchison/MRC Research Centre, Box 197, Cambridge CB2 0XZ, UK. cf366@MRC-CU.cam.ac.uk.
authors.forename: Christian
authors.initials: C
authors.lastname: Frezza
authors.forename: Tomer
authors.initials: T
authors.lastname: Shlomi
mesh_terms: D000262:Adenylyl Cyclases / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D000242:Cyclic AMP / Q000096:biosynthesis; D005649:Fumarate Hydratase / Q000172:deficiency* / Q000235:genetics; D015723:Gene Library; D005804:Genes, Lethal; D057809:HEK293 Cells; D057166:High-Throughput Screening Assays; D006801:Humans; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results
chemical_list: D034741:RNA, Small Interfering; D000242:Cyclic AMP; D005649:Fumarate Hydratase; D000262:Adenylyl Cyclases