Fatty Acid Synthase induced S6Kinase facilitates USP11-eIF4B complex formation for sustained oncogenic translation in DLBCL

Nat Commun. 2018 Feb 26;9(1):829. doi: 10.1038/s41467-018-03028-y.


Altered lipid metabolism and aberrant protein translation are strongly associated with cancerous outgrowth; however, the inter-regulation of these key processes is still underexplored in diffuse large B-cell lymphoma (DLBCL). Although fatty acid synthase (FASN) activity is reported to positively correlate with PI3K-Akt-mTOR pathway that can modulate protein synthesis, the precise impact of FASN inhibition on this process is still unknown. Herein, we demonstrate that attenuating FASN expression or its activity significantly reduces eIF4B (eukaryotic initiation factor 4B) levels and consequently overall protein translation. Through biochemical studies, we identified eIF4B as a bonafide substrate of USP11, which stabilizes and enhances eIF4B activity. Employing both pharmacological and genetic approaches, we establish that FASN-induced PI3K-S6Kinase signaling phosphorylates USP11 enhancing its interaction with eIF4B and thereby promoting oncogenic translation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • B-Lymphocytes / metabolism
  • B-Lymphocytes / pathology
  • Carcinogenesis / genetics
  • Carcinogenesis / metabolism
  • Carcinogenesis / pathology
  • Cell Line, Tumor
  • Eukaryotic Initiation Factors / genetics*
  • Eukaryotic Initiation Factors / metabolism
  • Fatty Acid Synthase, Type I / genetics*
  • Fatty Acid Synthase, Type I / metabolism
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Lipid Metabolism / genetics
  • Lymphoma, Large B-Cell, Diffuse / genetics
  • Lymphoma, Large B-Cell, Diffuse / metabolism
  • Lymphoma, Large B-Cell, Diffuse / pathology
  • Mice
  • Mice, Nude
  • Neoplasm Transplantation
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphorylation
  • Protein Binding
  • Protein Biosynthesis*
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • Ribosomal Protein S6 Kinases / genetics*
  • Ribosomal Protein S6 Kinases / metabolism
  • Signal Transduction
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism
  • Thiolester Hydrolases / genetics*
  • Thiolester Hydrolases / metabolism


  • Eukaryotic Initiation Factors
  • USP11 protein, human
  • eIF-4B
  • FASN protein, human
  • Fatty Acid Synthase, Type I
  • MTOR protein, human
  • Proto-Oncogene Proteins c-akt
  • Ribosomal Protein S6 Kinases
  • TOR Serine-Threonine Kinases
  • Thiolester Hydrolases