title: Systematic siRNA Screen Unmasks NSCLC Growth Dependence by Palmitoyltransferase DHHC5.
abstract: Protein S-palmitoylation is a widespread and dynamic posttranslational modification that regulates protein-membrane interactions, protein-protein interactions, and protein stability. A large family of palmitoyl acyl transferases, termed the DHHC family due to the presence of a common catalytic motif, catalyzes S-palmitoylation; the role of these enzymes in cancer is largely unexplored. In this study, an RNAi-based screen targeting all 23 members of the DHHC family was conducted to examine the effects on the growth in non-small cell lung cancer (NSCLC). Interestingly, siRNAs directed against DHHC5 broadly inhibited the growth of multiple NSCLC lines but not normal human bronchial epithelial cell (HBEC) lines. Silencing of DHHC5 by lentivirus-mediated expression of DHHC5 shRNAs dramatically reduced in vitro cell proliferation, colony formation, and cell invasion in a subset of cell lines that were examined in further detail. The phenotypes were restored by transfection of a wild-type DHHC5 plasmid but not by a plasmid expressing a catalytically inactive DHHC5. Tumor xenograft formation was severely inhibited by DHHC5 knockdown and rescued by DHHC5 expression, using both a conventional and tetracycline-inducible shRNA. These data indicate that DHHC5 has oncogenic capacity and contributes to tumor formation in NSCLC, thus representing a potential novel therapeutic target.
  
  
  CONCLUSIONS
  Inhibitors of DHHC5 enzyme activity may inhibit non-small cell lung cancer growth.
authors.affiliation: The Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Hui
authors.initials: H
authors.lastname: Tian
authors.affiliation: The Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas. Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Jui-Yun
authors.initials: JY
authors.lastname: Lu
authors.affiliation: The Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Chunli
authors.initials: C
authors.lastname: Shao
authors.affiliation: The Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Huffman
authors.affiliation: The Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Carstens
authors.affiliation: The Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Jill E
authors.initials: JE
authors.lastname: Larsen
authors.affiliation: The Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Luc
authors.initials: L
authors.lastname: Girard
authors.affiliation: Department of Translational Molecular Pathology, University of Texas, MD Anderson Cancer Center, Houston, Texas.
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Translational Molecular Pathology, University of Texas, MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jaime
authors.initials: J
authors.lastname: Rodriguez-Canales
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Eugene P
authors.initials: EP
authors.lastname: Frenkel
authors.affiliation: Department of Translational Molecular Pathology, University of Texas, MD Anderson Cancer Center, Houston, Texas.
authors.forename: Ignacio I
authors.initials: II
authors.lastname: Wistuba
authors.affiliation: The Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas. Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas. Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: John D
authors.initials: JD
authors.lastname: Minna
authors.affiliation: The Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas. Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas. sandra.hofmann@utsouthwestern.edu.
authors.forename: Sandra L
authors.initials: SL
authors.lastname: Hofmann
mesh_terms: D000217:Acyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D009368:Neoplasm Transplantation; D034741:RNA, Small Interfering / Q000378:metabolism*
chemical_list: D008565:Membrane Proteins; D034741:RNA, Small Interfering; D000217:Acyltransferases; C000604430:ZDHHC5 protein, human