Par6G suppresses cell proliferation and is targeted by loss-of-function mutations in multiple cancers

Oncogene. 2016 Mar 17;35(11):1386-98. doi: 10.1038/onc.2015.196. Epub 2015 Jun 15.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Apoptosis / genetics
  • Carcinogenesis / genetics*
  • Cell Line, Tumor
  • Cell Proliferation / genetics*
  • Epithelial Cells / cytology
  • Epithelial Cells / metabolism*
  • Humans
  • Mutation / genetics
  • Neoplasms, Glandular and Epithelial / genetics*
  • Neoplasms, Glandular and Epithelial / pathology
  • Phosphatidylinositol 3-Kinase / metabolism
  • Protein-Serine-Threonine Kinases / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • Proto-Oncogene Proteins c-myc / genetics
  • RNA Interference
  • RNA, Small Interfering / genetics
  • Wnt Proteins / genetics
  • Wnt Signaling Pathway / genetics

Substances

  • Adaptor Proteins, Signal Transducing
  • MYC protein, human
  • PARD6A protein, human
  • Proto-Oncogene Proteins c-myc
  • RNA, Small Interfering
  • Wnt Proteins
  • Phosphatidylinositol 3-Kinase
  • Hippo protein, human
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt