Oncotarget

Research Papers:

Inhibition of SIRT2 in merlin/NF2-mutant Schwann cells triggers necrosis

Alejandra M. Petrilli, Marga Bott and Cristina Fernández-Valle _

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Oncotarget. 2013; 4:2354-2365. https://doi.org/10.18632/oncotarget.1422

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Abstract

Alejandra M. Petrilli1, Marga Bott1, and Cristina Fernández-Valle1

1 Department of Biomedical Science, College of Medicine, University of Central Florida, Lake Nona-Orlando, Florida, USA

Correspondence:

Cristina Fernández-Valle, email:

Keywords: Neurofibromatosis Type2; high-throughput screen; SIRT2; acetylation, merlin, tumor suppressor, AGK2

Received: September 18, 2013 Accepted: November 14, 2013 Published: November 15, 2013

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.


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