ATRT-12. TARGETING SIRT2 IN SMARCB1 DEFICIENT ATRT. Issue 2 (22nd June 2018)

• Record Type: Journal Article
• Authors: Alimova, Irina; Venkataraman, Sujatha; Pierce, Angela M; Birks, Diane; Vibhakar, Rajeev; Foreman, Nicholas K; Yang, Min; Ling, Hinning
• Is Part Of: Neuro-oncology. Volume 20:Issue 2(2018)supplement 2
• Page Start: i29
• Page End: i30
• Publication Date: 2018-06-22
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noy059.011
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: Atypical Teratoid Rhabdoid Tumor (ATRT) is a highly aggressive and malignant pediatric brain tumor with poor outcomes. The central mechanism of ATRT tumorigenesis is SMARCB1 deficiency that leads to epigenetic dysregulation. To identify key epigenetic regulators that co-operate with SMARB1 deficiency and contribute to the tumorigenesis of ATRT, we performed an RNAi-based functional genomic screen. We targeted 406 genes associated with epigenetic regulation in ATRT cell lines. This screening revealed Sirtuin2 (SIRT2) as one of the top targets required for continued cell growth. SIRT2 is an NAD(+) (nicotinamide adenine dinucleotide)-dependent deacetylase and involved in the direct deacetylation of α-tubulin and histone H4. Inhibition of SIRT2 promotes c-Myc ubiquitination and degradation. C-Myc is an oncogene and highly expressed in ATRT, so SIRT2 is a promising target to treat c-Myc driven cancers. Genetic inactivation of SIRT2 with shRNA significantly suppressed ATRT cell growth, decreased c-Myc expression and activated p53. Recent studies suggest that targeting SIRT2 by small molecule inhibitors is a promising approach to tumor therapy. We found that chemical inhibition SIRT2 with AGK2, Tenovin6 and Thiomyristoyl (TM) significantly decreased cells growth, inhibited clonogenic potential, suppressed c-Myc level, and decreased S-phase length. In vivo, Tenovin6 and TM limited ATRT tumor growth both in flank and in intracranial mouse model due to increased apoptosis as measured by cleaved caspase 3 and decreased ki67 proliferative index. Moreover, TM treatment increased mice survival. In summary, we demonstrated that ATRT can be targeted by chemical or genetic SIRT2 inhibition.