Title

Inhibition Of Sirt2 In Merlin/Nf2-Mutant Schwann Cells Triggers Necrosis

Keywords

Acetylation; AGK2; Merlin; Neurofibromatosis Type2; high-throughput screen; SIRT2; Tumor suppressor

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.

Publication Date

1-1-2013

Publication Title

Oncotarget

Volume

4

Issue

12

Number of Pages

2354-2365

Document Type

Article

Personal Identifier

scopus

DOI Link

https://doi.org/10.18632/oncotarget.1422

Socpus ID

84891949982 (Scopus)

Source API URL

https://api.elsevier.com/content/abstract/scopus_id/84891949982

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