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PDCD4 is a CSL associated protein with a transcription repressive function in cancer associated fibroblast activation

Seung-Hee Jo1,2, Dong Eun Kim3, Andrea Clocchiatti1,2

  • 1Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, MA, USA.

Oncotarget
|August 20, 2016
PubMed

Insights

Programmed Cell Death 4 (PDCD4) interacts with CSL to suppress skin fibroblast senescence and cancer-associated fibroblast activation. Both proteins are downregulated in skin cancer, suggesting PDCD4’s role in controlling fibroblast to CAF conversion.

Area of Science:

  • Molecular Biology
  • Dermatology
  • Cancer Research

Background:

  • The Notch/CSL pathway is crucial for skin homeostasis and cancer development.
  • CSL, a key Notch signaling effector, represses stromal fibroblast senescence and Cancer Associated Fibroblast (CAF) activation.
  • Proteins interacting with CSL in this context remain largely unidentified.

Purpose of the Study:

  • To identify proteins interacting with CSL in the context of skin homeostasis and carcinogenesis.
  • To investigate the role of Programmed Cell Death 4 (PDCD4) in regulating dermal fibroblast senescence and CAF activation.
  • To determine the expression levels of PDCD4 in premalignant and malignant skin lesions.

Main Methods:

  • Co-immunoprecipitation assays to identify CSL-interacting proteins.
  • Analysis of PDCD4 and CSL expression in skin biopsies.
  • Functional assays to assess the role of PDCD4 in fibroblast senescence and CAF activation.
  • Chromatin immunoprecipitation to determine PDCD4 localization at target gene binding sites.

Main Results:

  • Programmed Cell Death 4 (PDCD4) was identified as a CSL-interacting protein.
  • PDCD4, similar to CSL, suppresses dermal fibroblast senescence and CAF activation.
  • Both PDCD4 and CSL expression are reduced in actinic keratosis (AK) and squamous cell carcinoma (SCC) stromal fibroblasts.
  • PDCD4 localizes to CSL binding sites on CAF marker and Notch/CSL target genes, suppressing their expression in a fibroblast-specific manner.

Conclusions:

  • PDCD4 associates with CSL and contributes to the suppression of fibroblast senescence and CAF activation.
  • PDCD4 is a component of the CSL repressive complex that negatively regulates the conversion of stromal fibroblasts into CAFs.
  • Downregulation of PDCD4 in skin cancer may contribute to CAF activation and tumor progression.
Keywords:
CAFsNotch/CSL signalingPDCD4squamous cancertranscription repression

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