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Par6G suppresses cell proliferation and is targeted by loss-of-function mutations in multiple cancers
E Marques1, J I Englund1, T A Tervonen1
1Cancer Cell Circuitry Laboratory, Research programs unit, Translational Cancer Biology and Institute of Biomedicine, University of Helsinki, Finland.
Oncogene
|June 16, 2015
Summary
Epithelial structure integrity is crucial for controlling cell proliferation. Disrupting this, particularly through pathways like Hippo and Wnt, can drive cancer by affecting cell cycle regulation.
Area of Science:
- Cell Biology
- Cancer Biology
- Developmental Biology
Background:
- Epithelial structure normally suppresses cell proliferation.
- Pathways linking epithelial integrity to cell proliferation control and tumorigenesis are not well understood.
- Understanding these links is vital for cancer research.
Purpose of the Study:
- To investigate the impact of compromised epithelial integrity on normal and oncogenic Myc-driven proliferation.
- To identify genes and pathways regulating epithelial integrity and cell proliferation.
- To explore the role of Par6G in epithelial cell cycle regulation and cancer.
Main Methods:
- Utilized three-dimensional mammary epithelial organoid culture.
- Performed systematic silencing of 34 human homologs of Drosophila genes involved in epithelial integrity.
- Investigated functional interactions with Myc, RhoA, Par6, and the PI3K/Akt pathway.
Main Results:
- Compromised epithelial integrity significantly impacts Myc-driven proliferation.
- Genes in apico-basal polarity, Wnt, Hippo pathways, and actin dynamics regulate organoid size, integrity, and proliferation.
- Perturbations revealed RhoA-dependent synthetic lethality and Par6-dependent cell cycle effects.
- Par6G negatively regulates the PI3K/Akt pathway and epithelial cell proliferation.
- Par6G gene inactivation is frequent in epithelial cancers.
Conclusions:
- Epithelial structure determinants regulate cell proliferation through conserved, cancer-relevant pathways.
- These regulatory circuits are essential for epithelial cell cycle restriction.
- Identified potential therapeutic targets for epithelial cancers.
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