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

Area of Science:

• Oncology
• Genetics
• Molecular Biology

Background:

• Neurofibromatosis Type 2 (NF2) is a genetic disorder caused by mutations in the NF2 gene, leading to tumor formation.
• The NF2 gene encodes the tumor suppressor protein merlin, which regulates critical cellular signaling pathways.
• Currently, no specific drug therapies exist for NF2, highlighting an unmet medical need.

Purpose of the Study:

• To identify potential therapeutic compounds for NF2 by screening for agents that reduce the viability of Nf2-inactivated mouse Schwann cells (MSC).
• To investigate the role of sirtuin 2 (SIRT2) in NF2 schwannoma pathogenesis.

Main Methods:

• A pilot high-throughput screen of the Library of Pharmacologically Active Compounds was conducted using mouse Schwann cells with Nf2 inactivation.
• The SIRT2 inhibitor AGK2 was identified as a candidate compound.
• Expression levels of SIRT2 and overall lysine acetylation were compared between merlin-mutant and wild-type MSCs.

Main Results:

• AGK2, a SIRT2 inhibitor, was identified as a compound that reduces merlin-mutant MSC viability in a dose-dependent manner.
• Merlin-mutant MSCs exhibited higher SIRT2 expression and lower overall lysine acetylation compared to wild-type controls.
• SIRT2 inhibition in merlin-mutant MSCs led to necrosis, indicated by lactate dehydrogenase and high mobility group box 1 release, without significant apoptosis, autophagy, or cell cycle arrest.

Conclusions:

• SIRT2 is upregulated in merlin-deficient Schwann cells and its inhibition selectively triggers necrosis in these cells.
• SIRT2 represents a promising therapeutic target for the development of novel drug therapies for Neurofibromatosis Type 2.