Complete Acid Ceramidase ablation prevents cancer-initiating cell formation in melanoma cells

Sci Rep. 2017 Aug 7;7(1):7411. doi: 10.1038/s41598-017-07606-w.


Acid ceramidase (AC) is a lysosomal cysteine hydrolase that catalyzes the conversion of ceramide into fatty acid and sphingosine. This reaction lowers intracellular ceramide levels and concomitantly generates sphingosine used for sphingosine-1-phosphate (S1P) production. Since increases in ceramide and consequent decreases of S1P reduce proliferation of various cancers, AC might offer a new target for anti-tumor therapy. Here we used CrispR-Cas9-mediated gene editing to delete the gene encoding for AC, ASAH1, in human A375 melanoma cells. ASAH1-null clones show significantly greater accumulation of long-chain saturated ceramides that are substrate for AC. As seen with administration of exogenous ceramide, AC ablation blocks cell cycle progression and accelerates senescence. Importantly, ASAH1-null cells also lose the ability to form cancer-initiating cells and to undergo self-renewal, which is suggestive of a key role for AC in maintaining malignancy and self-renewal of invasive melanoma cells. The results suggest that AC inhibitors might find therapeutic use as adjuvant therapy for advanced melanoma.

MeSH terms

  • Acid Ceramidase / genetics*
  • CRISPR-Associated Protein 9
  • Cell Line, Tumor
  • Cell Proliferation*
  • Cellular Senescence*
  • Ceramides / analysis*
  • Clustered Regularly Interspaced Short Palindromic Repeats
  • Gene Knockout Techniques*
  • Humans
  • Lysophospholipids / analysis
  • Melanocytes / enzymology*
  • Melanocytes / metabolism*
  • Sphingosine / analogs & derivatives
  • Sphingosine / analysis


  • Ceramides
  • Lysophospholipids
  • sphingosine 1-phosphate
  • CRISPR-Associated Protein 9
  • ASAH1 protein, human
  • Acid Ceramidase
  • Sphingosine