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

Bandish Kapadia; Nahid M Nanaji; Kavita Bhalla; Binny Bhandary; Rena Lapidus; Afshin Beheshti; Andrew M Evens; Ronald B Gartenhaus

doi:10.1038/s41467-018-03028-y

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.

Authors

Bandish Kapadia¹, Nahid M Nanaji^{2

3}, Kavita Bhalla¹, Binny Bhandary¹, Rena Lapidus¹, Afshin Beheshti⁴, Andrew M Evens⁴, Ronald B Gartenhaus^{5

6}

Affiliations

¹ Department of Medicine, Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, MD, 21201, USA.
² Department of Veteran Affairs, Maryland Healthcare System, Baltimore, MD 21201, USA.
³ University of Maryland Medical Center, Baltimore, MD, 21201, USA.
⁴ Division of Hematology/Oncology, Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA, 02111, USA.
⁵ Department of Medicine, Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, MD, 21201, USA. [email protected].
⁶ Veterans Administration Medical Center, Baltimore, MD, 21201, USA. [email protected].

Abstract

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

Substances

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding