title: Inhibition of SIRT2 in merlin/NF2-mutant Schwann cells triggers necrosis.
abstract: Mutations in the NF2 gene cause Neurofibromatosis Type 2 (NF2), a disorder characterized by the development of schwannomas, meningiomas and ependymomas in the nervous system. Merlin, a tumor suppressor encoded by the NF2 gene, modulates activity of many essential signaling pathways. Yet despite increasing knowledge of merlin function, there are no NF2 drug therapies. In a pilot high-throughput screen of the Library of Pharmacologically Active Compounds, we assayed for compounds capable of reducing viability of mouse Schwann cells (MSC) with Nf2 inactivation as a cellular model for human NF2 schwannomas. AGK2, a SIRT2 (sirtuin 2) inhibitor, was identified as a candidate compound. SIRT2 is one of seven mammalian sirtuins that are NAD+-dependent protein deacetylases. We show that merlin-mutant MSC have higher expression levels of SIRT2 and lower levels of overall lysine acetylation than wild-type control MSC. Pharmacological inhibition of SIRT2 decreases merlin-mutant MSC viability in a dose dependent manner without substantially reducing wild-type MSC viability. Inhibition of SIRT2 activity in merlin-mutant MSC is accompanied by release of lactate dehydrogenase and high mobility group box 1 protein into the medium in the absence of significant apoptosis, autophagy, or cell cycle arrest. These findings suggest that SIRT2 inhibition triggers necrosis of merlin-mutant MSCs and that SIRT2 is a potential NF2 drug target.
authors.affiliation: Department of Biomedical Science, College of Medicine, University of Central Florida, Lake Nona-Orlando, Florida, USA.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Petrilli
authors.forename: Marga
authors.initials: M
authors.lastname: Bott
authors.forename: Cristina
authors.initials: C
authors.lastname: Fernández-Valle
mesh_terms: D000107:Acetylation; D000818:Animals; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D016147:Genes, Tumor Suppressor; D057166:High-Throughput Screening Assays; D006801:Humans; D051379:Mice; D009336:Necrosis; D016518:Neurofibromatosis 2 / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D025581:Neurofibromin 2 / Q000235:genetics* / Q000378:metabolism; D012583:Schwann Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D015398:Signal Transduction; D056565:Sirtuin 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D025581:Neurofibromin 2; C474199:SIRT2 protein, human; D056565:Sirtuin 2