An Essential Role for the Tumor-Suppressor Merlin in Regulating Fatty Acid Synthesis

Dina S Stepanova, Galina Semenova, Yin-Ming Kuo, Andrew J Andrews, Sylwia Ammoun, C Oliver Hanemann, Jonathan Chernoff
Cancer Research 2017 September 15, 77 (18): 5026-5038
Neurofibromatosis type 2 (NF2) is an autosomal dominant disorder characterized by the development of multiple tumors in the central nervous system, most notably schwannomas, and meningiomas. Mutational inactivation of the NF2 gene encoding the protein Merlin is found in most sporadic and inherited schwannomas, but the molecular mechanisms underlying neoplastic changes in schwannoma cells remain unclear. We report here that Nf2-deficient cells display elevated expression levels of key enzymes involved in lipogenesis and that this upregulation is caused by increased activity of Torc1. Inhibition or knockdown of fatty acid synthase (FASN), the enzyme that catalyzes the formation of palmitic acid from malonyl-CoA, drove NF2 -deficient cells into apoptosis. Treatment of NF2 -mutant cells with agents that inhibit the production of malonyl-CoA reduced their sensitivity to FASN inhibitors. Collectively, these results suggest that the altered lipid metabolism found in NF2 -mutant cells renders them sensitive to elevated levels of malonyl-CoA, as occurs following blockade of FASN, suggesting new targeted strategies in the treatment of NF2 -deficient tumors. Cancer Res; 77(18); 5026-38. ©2017 AACR .

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