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Autophagy Controls CSL/RBPJκ Stability through a p62/SQSTM1-Dependent Mechanism

Sandro Goruppi1, Seung-Hee Jo1, Csaba Laszlo2

  • 1Cutaneous Biology Research Center, Massachusetts General Hospital, 149 Bldg. 13(th) St. Charlestown, MA 02129, USA; Department of Dermatology, Harvard Medical School, Boston, MA 02125, USA.

Cell Reports
|September 21, 2018
PubMed

Insights

Cancer-associated fibroblasts (CAFs) drive tumor progression. Autophagy down-regulates CSL protein via p62, impacting CAF activation and offering new cancer treatment targets.

Area of Science:

  • Cell Biology
  • Cancer Biology
  • Tumor Microenvironment

Background:

  • Cancer-associated fibroblasts (CAFs) play a critical role throughout tumor progression.
  • CSL/RBPJκ is a transcription factor that suppresses CAF activation, metabolic reprogramming, and autophagy.
  • The regulation of CSL protein turnover, particularly within the tumor microenvironment, remains poorly understood.

Purpose of the Study:

  • To investigate the mechanisms regulating CSL protein turnover in the context of autophagy.
  • To elucidate the functional significance of CSL protein regulation in CAFs.
  • To explore potential therapeutic strategies targeting the CAF-CSL-autophagy axis.

Main Methods:

  • Investigated CSL protein and mRNA levels in human dermal fibroblasts (HDFs) under autophagy-inducing conditions.
  • Utilized genetic and pharmacologic approaches to modulate autophagic machinery.
  • Examined the interaction between CSL and p62/SQSTM1 using co-immunoprecipitation.
  • Assessed CSL and p62 levels in skin cancer-derived CAFs with varying autophagy levels.

Main Results:

  • Autophagy-inducing conditions in HDFs decreased CSL protein levels without affecting mRNA levels.
  • Inhibition of autophagy prevented CSL down-modulation.
  • Endogenous CSL was found to associate with p62/SQSTM1, a key mediator of CSL degradation by autophagy.
  • Both CSL and p62 levels were reduced in CAFs with elevated autophagy, characteristic of skin cancers.
  • Elevating cellular CSL levels led to p62 stabilization and reduced autophagy.

Conclusions:

  • Autophagy initiates a mechanism for CSL protein down-modulation through p62/SQSTM1.
  • This regulatory axis is dysregulated in cancer-associated fibroblasts, with increased autophagy leading to lower CSL and p62 levels.
  • Targeting this autophagy-initiated CSL down-modulation pathway presents a potential strategy for stroma-focused cancer prevention and treatment.
Keywords:
CAFCSL/RBPJκautophagycancer-associated fibroblastp62/SQSTM1protein turnover

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