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Merlin/NF2-Lin28B-let-7 Is a Tumor-Suppressive Pathway that Is Cell-Density Dependent and Hippo Independent

Hiroki Hikasa1, Yoshitaka Sekido2, Akira Suzuki1

  • 1Division of Cancer Genetics, Medical Institute of Bioregulation, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.

Cell Reports
|March 22, 2016
PubMed

Insights

Merlin/NF2 tumor suppressor activity is cell-density dependent. It sequesters Lin28B at high cell density, allowing let-7 miRNA maturation and inhibiting cell growth, independent of the Hippo pathway.

Area of Science:

  • Cell biology
  • Molecular oncology
  • Tumor suppressor mechanisms

Background:

  • Contact inhibition of proliferation is crucial for tissue homeostasis.
  • Dysregulation of Merlin/NF2, a tumor suppressor, contributes to cancer development.
  • The precise mechanism by which Merlin/NF2 signaling suppresses tumors, particularly in response to cell-cell contact, remains incompletely understood.

Purpose of the Study:

  • To elucidate the downstream targets and signaling pathways regulated by Merlin/NF2 in response to cell density.
  • To investigate the role of Lin28B in Merlin/NF2-mediated contact inhibition.
  • To determine if Merlin/NF2's tumor suppressive function is linked to the Hippo pathway.

Main Methods:

  • Investigated Merlin/NF2 phosphorylation status and binding interactions with Lin28B at varying cell densities.
  • Utilized functional assays to assess the impact of Lin28B on pri-let-7 miRNA maturation and cell proliferation.
  • Examined the subcellular localization of Lin28B in response to cell-cell contact and Merlin/NF2 activity.
  • Assessed the dependency of Merlin/NF2 signaling on YAP1/TAZ and the Hippo pathway.

Main Results:

  • Identified Lin28B, an inhibitor of let-7 microRNAs (miRNAs), as a novel downstream target of Merlin/NF2.
  • Demonstrated that at low cell density, Merlin/NF2 is phosphorylated, allowing Lin28B nuclear entry and inhibition of let-7 miRNA maturation, promoting cell growth.
  • Showed that cell-cell contact induces Merlin/NF2 dephosphorylation, leading to cytoplasmic sequestration of Lin28B and restoration of let-7 miRNA maturation.
  • Confirmed that this Merlin/NF2-mediated tumor suppression is independent of YAP1/TAZ and the Hippo pathway.

Conclusions:

  • Merlin/NF2 exerts tumor-suppressive effects through a cell-density-dependent mechanism involving the regulation of let-7 miRNA maturation via Lin28B.
  • This pathway operates independently of the canonical Hippo pathway, highlighting a novel mode of tumor suppression.
  • Understanding this Merlin/NF2-Lin28B-let-7 axis offers potential therapeutic targets for cancers with disrupted contact inhibition.
Keywords:
Hippo pathwayLin28BMerlin/NF2cell contactlet-7microRNA

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