Systematic siRNA screen unmasks NSCLC growth dependence by palmitoyltransferase DHHC5

Hui Tian, Jui Yun Lu, Chunli Shao, Kenneth E. Huffman, Ryan M. Carstens, Jill E. Larsen, Luc Girard, Hui Liu, Jaime Rodriguez-Canales, Eugene P. Frenkel, Ignacio I. Wistuba, John D. Minna, Sandra L. Hofmann

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Protein S-palmitoylation is a widespread and dynamic posttranslationalmodification that regulates protein-membrane interactions, protein-protein interactions, and protein stability. A large family of palmitoyl acyl transferases, termed theDHHCfamily 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, anRNAi-based screen targeting all 23members 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 byDHHC5knockdownand rescued by DHHC5 expression, using both a conventional and tetracycline-inducible shRNA. These data indicate thatDHHC5has oncogenic capacity and contributes to tumor formation in NSCLC, thus representing a potential novel therapeutic target. Implications: Inhibitors of DHHC5 enzyme activity may inhibit non-small cell lung cancer growth. Mol Cancer Res; 13(4); 784-94.

Original languageEnglish (US)
Pages (from-to)784-794
Number of pages11
JournalMolecular Cancer Research
Volume13
Issue number4
DOIs
StatePublished - Apr 1 2015

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Non-Small Cell Lung Carcinoma
Small Interfering RNA
Lipoylation
Growth
Neoplasms
Plasmids
Cell Line
Lentivirus
Protein Stability
Protein S
Enzyme Inhibitors
Transferases
Tetracycline
Heterografts
Transfection
Membrane Proteins
Proteins
Epithelial Cells
Cell Proliferation
Phenotype

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Oncology

Cite this

Systematic siRNA screen unmasks NSCLC growth dependence by palmitoyltransferase DHHC5. / Tian, Hui; Lu, Jui Yun; Shao, Chunli; Huffman, Kenneth E.; Carstens, Ryan M.; Larsen, Jill E.; Girard, Luc; Liu, Hui; Rodriguez-Canales, Jaime; Frenkel, Eugene P.; Wistuba, Ignacio I.; Minna, John D.; Hofmann, Sandra L.

In: Molecular Cancer Research, Vol. 13, No. 4, 01.04.2015, p. 784-794.

Research output: Contribution to journalArticle

Tian, H, Lu, JY, Shao, C, Huffman, KE, Carstens, RM, Larsen, JE, Girard, L, Liu, H, Rodriguez-Canales, J, Frenkel, EP, Wistuba, II, Minna, JD & Hofmann, SL 2015, 'Systematic siRNA screen unmasks NSCLC growth dependence by palmitoyltransferase DHHC5', Molecular Cancer Research, vol. 13, no. 4, pp. 784-794. https://doi.org/10.1158/1541-7786.MCR-14-0608
Tian, Hui ; Lu, Jui Yun ; Shao, Chunli ; Huffman, Kenneth E. ; Carstens, Ryan M. ; Larsen, Jill E. ; Girard, Luc ; Liu, Hui ; Rodriguez-Canales, Jaime ; Frenkel, Eugene P. ; Wistuba, Ignacio I. ; Minna, John D. ; Hofmann, Sandra L. / Systematic siRNA screen unmasks NSCLC growth dependence by palmitoyltransferase DHHC5. In: Molecular Cancer Research. 2015 ; Vol. 13, No. 4. pp. 784-794.
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