SIRT2 is a regulator of the differentiation block driven by SMARCB1 loss in ATRT [bulk RNA-seq]

Background. Atypical teratoid rhabdoid tumor (ATRT) is a highly aggressive brain tumor of childhood with a poor overall survival. The salient molecular feature of ATRT is the loss of SMARCB1 which results in epigenetic dysregulation of the genome. SMARCB1 loss affects lineage commitment and differentiation by controlling gene expression. We hypothesized that additional epigenetic factors co-operate with SMARCB1 loss to control cell self-renewal and drive ATRT. We identified SIRT2 as a primary dependency in ATRT. Using a combination of RNA-seq, CUT&RUN and single RNA sequencing in model systems ATRT, we observed genome-wide reorganization of active chromatin and significantly changes in genes expression in ATRT cells with genetic (with shRNA) or chemical (with Tenovin or Thiomyristoyl (TM) ) SIRT2 deactivation. Single-cell RNA transcriptome analysis of xenograft tumors revealed the elimination of tumor cells expressing stem cell genes and expansion of tumor cells expressing differentiated genes in vivo. Furthermore, SIRT2 inhibition induced apoptosis, decreased tumor growth and prolonged survival in orthotopic xenograft models. In summary we demonstrated that SIRT2 inhibition is a molecular vulnerability in SMARCB1-deleted tumors with therapeutic potential. Overall design: Bulk RNA-Seq data comparing gene expression in pediatric Atypical teratoid rhabdoid tumor (ATRT) BT16 cells treated with Tenovin (1um of Tenovin for 72 hours) and DMSO. Bulk RNA-Seq data comparing gene expression in pediatric ATRT with SIRT2 knockdown(shSIRT) vs. vector control shRNA (shNULL).