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Yin-Yang strands of PCAF/Hedgehog axis in cancer control

Paola Infante1, Gianluca Canettieri2, Alberto Gulino3

  • 1Center for Life Nanoscience (CLNS), Italian Institute of Technology-Sapienza, 00161 Rome, Italy.

Trends in Molecular Medicine
|June 8, 2014
PubMed

Insights

PCAF, a protein with acetyltransferase and ubiquitylation functions, regulates gene expression. The PCAF/GLI1 axis is a potential therapeutic target for Hedgehog-dependent tumors due to its role in development and cancer.

Area of Science:

  • Molecular Biology
  • Epigenetics
  • Cancer Biology

Background:

  • PCAF (p300/CBP associated factor) possesses both acetyltransferase and ubiquitylation activities.
  • These activities regulate gene expression in response to cellular stress and growth signals.
  • The Hedgehog signaling pathway is crucial for tissue development, stemness, and tumorigenesis.

Purpose of the Study:

  • To investigate the dual role of PCAF in regulating the Hedgehog signaling pathway.
  • To elucidate the mechanisms by which PCAF influences GLI1, a key mediator of Hedgehog signaling.
  • To evaluate the PCAF/GLI1 axis as a potential therapeutic target in Hedgehog-dependent cancers.

Main Methods:

  • Analysis of PCAF's histone acetyltransferase activity at target gene promoters.
  • Investigation of PCAF's ubiquitylation activity on GLI1.
  • Assessment of GLI1 protein levels and proteolysis.
  • Evaluation of therapeutic potential in relevant cancer models.

Main Results:

  • PCAF modulates Hedgehog/GLI1 target gene expression via histone acetylation.
  • PCAF directly ubiquitylates GLI1, leading to its proteolysis.
  • The PCAF/GLI1 axis plays a critical role in Hedgehog signaling.

Conclusions:

  • PCAF exhibits a dual regulatory role in the Hedgehog pathway through acetylation and ubiquitylation.
  • Targeting the PCAF/GLI1 axis offers a promising therapeutic strategy for Hedgehog-driven tumors.
  • Understanding PCAF's function provides insights into developmental processes and cancer progression.
Keywords:
E3-ubiquitin ligaseHedgehogPCAFacetyltransferasecancerp53

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