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ZNF768 links oncogenic RAS to cellular senescence

Romain Villot1,2, Audrey Poirier1,2, Inan Bakan1,2

  • 1Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec (CRIUCPQ), Faculté de Médecine, Université Laval, Québec, QC, Canada.

Nature Communications
|August 18, 2021
PubMed

Insights

ZNF768 protein levels decrease with RAS activation, impairing cell proliferation and inducing senescence. Overexpression of ZNF768 bypasses senescence by repressing the p53 pathway, promoting tumor growth.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • RAS GTPases are crucial regulators of cell fate, influencing proliferation and senescence.
  • The precise mechanisms integrating RAS signaling to balance cell division and senescence remain unclear.

Purpose of the Study:

  • To identify novel regulators of the balance between cell proliferation and senescence.
  • To elucidate the role of ZNF768 in RAS-mediated cell fate decisions.

Main Methods:

  • Investigated ZNF768 protein stability and expression in response to RAS activation.
  • Assessed the impact of ZNF768 depletion and overexpression on cell proliferation and senescence.
  • Analyzed ZNF768 interaction with and regulation of the p53 pathway.
  • Examined ZNF768 expression in human tumors using cancer genomics and immunohistochemistry.

Main Results:

  • ZNF768 is a phosphoprotein destabilized by RAS activation.
  • ZNF768 depletion induces senescence by affecting cell cycle regulators and p53 targets.
  • ZNF768 levels decline during replicative, stress, and oncogene-induced senescence.
  • ZNF768 overexpression bypasses RAS-induced senescence by inhibiting p53 phosphorylation and activity.
  • ZNF768 is frequently amplified or overexpressed in tumors.

Conclusions:

  • ZNF768 acts as a critical link between oncogenic RAS signaling and cell fate control.
  • ZNF768 dysregulation contributes to senescence evasion, sustained proliferation, and malignant transformation.
  • Targeting ZNF768 may offer therapeutic strategies for cancers driven by RAS pathway activation.

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