title: Par6G suppresses cell proliferation and is targeted by loss-of-function mutations in multiple cancers.
abstract: Differentiated epithelial structure communicates with individual constituent epithelial cells to suppress their proliferation activity. However, the pathways linking epithelial structure to cessation of the cell proliferation machinery or to unscheduled proliferation in the context of tumorigenesis are not well defined. Here we demonstrate the strong impact of compromised epithelial integrity on normal and oncogenic Myc-driven proliferation in three-dimensional mammary epithelial organoid culture. Systematic silencing of 34 human homologs of Drosophila genes, with previously established functions in control of epithelial integrity, demonstrates a role for human genes of apico-basal polarity, Wnt and Hippo pathways and actin dynamics in regulation of the size, integrity and cell proliferation in organoids. Perturbation of these pathways leads to diverse functional interactions with Myc: manifested as a RhoA-dependent synthetic lethality and Par6-dependent effects on the cell cycle. Furthermore, we show a role for Par6G as a negative regulator of the phosphatidylinositol 3'-kinase/phosphoinositide-dependent protein kinase 1/Akt pathway and epithelial cell proliferation and evidence for frequent inactivation of Par6G gene in epithelial cancers. The findings demonstrate that determinants of epithelial structure regulate the cell proliferation activity via conserved and cancer-relevant regulatory circuitries, which are important for epithelial cell cycle restriction and may provide new targets for therapeutic intervention.
authors.affiliation: Cancer Cell Circuitry Laboratory, Research programs unit, Translational Cancer Biology and Institute of Biomedicine, University of Helsinki, Finland.
authors.forename: E
authors.initials: E
authors.lastname: Marques
authors.affiliation: Cancer Cell Circuitry Laboratory, Research programs unit, Translational Cancer Biology and Institute of Biomedicine, University of Helsinki, Finland.
authors.forename: J I
authors.initials: JI
authors.lastname: Englund
authors.affiliation: Cancer Cell Circuitry Laboratory, Research programs unit, Translational Cancer Biology and Institute of Biomedicine, University of Helsinki, Finland.
authors.forename: T A
authors.initials: TA
authors.lastname: Tervonen
authors.affiliation: Cancer Cell Circuitry Laboratory, Research programs unit, Translational Cancer Biology and Institute of Biomedicine, University of Helsinki, Finland.
authors.forename: E
authors.initials: E
authors.lastname: Virkunen
authors.affiliation: Systems Biology Laboratory, Genome-Scale Biology Program and Institute of Biomedicine, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
authors.forename: M
authors.initials: M
authors.lastname: Laakso
authors.affiliation: Cancer Cell Circuitry Laboratory, Research programs unit, Translational Cancer Biology and Institute of Biomedicine, University of Helsinki, Finland.
authors.forename: M
authors.initials: M
authors.lastname: Myllynen
authors.affiliation: Cancer Cell Circuitry Laboratory, Research programs unit, Translational Cancer Biology and Institute of Biomedicine, University of Helsinki, Finland.
authors.forename: A
authors.initials: A
authors.lastname: Mäkelä
authors.affiliation: Cancer Cell Circuitry Laboratory, Research programs unit, Translational Cancer Biology and Institute of Biomedicine, University of Helsinki, Finland.
authors.forename: M
authors.initials: M
authors.lastname: Ahvenainen
authors.affiliation: Genome-Scale Biology Program and Institute of Biomedicine, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
authors.forename: T
authors.initials: T
authors.lastname: Lepikhova
authors.affiliation: Genome-Scale Biology Program and Institute of Biomedicine, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
authors.forename: O
authors.initials: O
authors.lastname: Monni
authors.affiliation: Systems Biology Laboratory, Genome-Scale Biology Program and Institute of Biomedicine, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
authors.forename: S
authors.initials: S
authors.lastname: Hautaniemi
authors.affiliation: Cancer Cell Circuitry Laboratory, Research programs unit, Translational Cancer Biology and Institute of Biomedicine, University of Helsinki, Finland.
authors.forename: J
authors.initials: J
authors.lastname: Klefström
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D017209:Apoptosis / Q000235:genetics; D063646:Carcinogenesis / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics*; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D000090683:Hippo Signaling Pathway; D006801:Humans; D009154:Mutation / Q000235:genetics; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics* / Q000473:pathology; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D051153:Wnt Proteins / Q000235:genetics; D060449:Wnt Signaling Pathway / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C489427:MYC protein, human; C499657:PARD6A protein, human; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; D051153:Wnt Proteins; D058539:Phosphatidylinositol 3-Kinase; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt