title: Epithelial-to-mesenchymal transition drives a pro-metastatic Golgi compaction process through scaffolding protein PAQR11.
abstract: Tumor cells gain metastatic capacity through a Golgi phosphoprotein 3-dependent (GOLPH3-dependent) Golgi membrane dispersal process that drives the budding and transport of secretory vesicles. Whether Golgi dispersal underlies the pro-metastatic vesicular trafficking that is associated with epithelial-to-mesenchymal transition (EMT) remains unclear. Here, we have shown that, rather than causing Golgi dispersal, EMT led to the formation of compact Golgi organelles with improved ribbon linking and cisternal stacking. Ectopic expression of the EMT-activating transcription factor ZEB1 stimulated Golgi compaction and relieved microRNA-mediated repression of the Golgi scaffolding protein PAQR11. Depletion of PAQR11 dispersed Golgi organelles and impaired anterograde vesicle transport to the plasma membrane as well as retrograde vesicle tethering to the Golgi. The N-terminal scaffolding domain of PAQR11 was associated with key regulators of Golgi compaction and vesicle transport in pull-down assays and was required to reconstitute Golgi compaction in PAQR11-deficient tumor cells. Finally, high PAQR11 levels were correlated with EMT and shorter survival in human cancers, and PAQR11 was found to be essential for tumor cell migration and metastasis in EMT-driven lung adenocarcinoma models. We conclude that EMT initiates a PAQR11-mediated Golgi compaction process that drives metastasis.
authors.forename: Xiaochao
authors.initials: X
authors.lastname: Tan
authors.forename: Priyam
authors.initials: P
authors.lastname: Banerjee
authors.forename: Hou-Fu
authors.initials: HF
authors.lastname: Guo
authors.forename: Stephen
authors.initials: S
authors.lastname: Ireland
authors.forename: Daniela
authors.initials: D
authors.lastname: Pankova
authors.forename: Young-Ho
authors.initials: YH
authors.lastname: Ahn
authors.forename: Irodotos Michail
authors.initials: IM
authors.lastname: Nikolaidis
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.forename: Yanbin
authors.initials: Y
authors.lastname: Zhao
authors.forename: Yongming
authors.initials: Y
authors.lastname: Xue
authors.forename: Alan R
authors.initials: AR
authors.lastname: Burns
authors.forename: Jonathon
authors.initials: J
authors.lastname: Roybal
authors.forename: Don L
authors.initials: DL
authors.lastname: Gibbons
authors.forename: Tomasz
authors.initials: T
authors.lastname: Zal
authors.forename: Chad J
authors.initials: CJ
authors.lastname: Creighton
authors.forename: Daniel
authors.initials: D
authors.lastname: Ungar
authors.forename: Yanzhuang
authors.initials: Y
authors.lastname: Wang
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Kurie
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D058750:Epithelial-Mesenchymal Transition; D017353:Gene Deletion; D006056:Golgi Apparatus / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D000072417:Protein Domains; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism*; D000071799:Zinc Finger E-box-Binding Homeobox 1 / Q000235:genetics / Q000378:metabolism
chemical_list: C429024:GOLPH3 protein, human; D008565:Membrane Proteins; D035683:MicroRNAs; D009363:Neoplasm Proteins; D012334:RNA, Neoplasm; D011980:Receptors, Progesterone; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1