title: PORCN moonlights in a Wnt-independent pathway that regulates cancer cell proliferation.
abstract: Porcupine (PORCN) is a membrane-bound O-acyl transferase that is required for the palmitoylation of Wnt proteins, and that is essential in diverse Wnt pathways for Wnt-Wntless (WLS) binding, Wnt secretion, and Wnt signaling activity. We tested if PORCN was required for the proliferation of transformed cells. Knockdown of PORCN by multiple independent siRNAs results in a cell growth defect in a subset of epithelial cancer cell lines. The growth defect is transformation-dependent in human mammary epithelial (HMEC) cells. Additionally, inducible PORCN knockdown by two independent shRNAs markedly reduces the growth of established MDA-MB-231 cancers in orthotopic xenografts in immunodeficient mice. Unexpectedly, the proliferation defect resulting from loss of PORCN occurs in a Wnt-independent manner, as it is rescued by re-expression of catalytically inactive PORCN, and is not seen after RNAi-mediated knockdown of the Wnt carrier protein WLS, nor after treatment with the PORCN inhibitor IWP. Consistent with a role in a Wnt-independent pathway, knockdown of PORCN regulates a distinct set of genes that are not altered by other inhibitors of Wnt signaling. PORCN protein thus appears to moonlight in a novel signaling pathway that is rate-limiting for cancer cell growth and tumorigenesis independent of its enzymatic function in Wnt biosynthesis and secretion.
authors.affiliation: Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore, Singapore.
authors.forename: Tracy M
authors.initials: TM
authors.lastname: Covey
authors.forename: Simran
authors.initials: S
authors.lastname: Kaur
authors.forename: Tina
authors.initials: T
authors.lastname: Tan Ong
authors.forename: Kyle D
authors.initials: KD
authors.lastname: Proffitt
authors.forename: Yonghui
authors.initials: Y
authors.lastname: Wu
authors.forename: Patrick
authors.initials: P
authors.lastname: Tan
authors.forename: David M
authors.initials: DM
authors.lastname: Virshup
mesh_terms: D000217:Acyltransferases; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics / Q000473:pathology*; D043562:Receptors, G-Protein-Coupled; D015398:Signal Transduction / Q000235:genetics; D051153:Wnt Proteins / Q000378:metabolism*
chemical_list: C545200:Gpr177 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D043562:Receptors, G-Protein-Coupled; D051153:Wnt Proteins; D000217:Acyltransferases; C491188:PORCN protein, human