Data from SIRT2 Regulates the SMARCB1 Loss-Driven Differentiation Block in ATRT

作者：Irina Alimova, Dong Wang, John DeSisto, Etienne Danis, Senthilnath Lakshmanachetty, Eric Prince, Gillian Murdock, Angela Pierce, Andrew M. Donson, Ilango Balakrishnan, Natalie J. Serkova, Hening Lin, Nicholas K. Foreman, Nathan Dahl, Sujatha Venkataraman, Rajeev Vibhakar · 年份：2025 · DOI：10.1158/1541-7786.c.7854101 · 被引用次数：1 · 研究领域：RNA regulation and disease、Cancer Mechanisms and Therapy、Chromatin Remodeling and Cancer

<div>AbstractAn atypical teratoid rhabdoid tumor (ATRT) is a highly aggressive pediatric brain tumor driven by 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 cooperate with SMARCB1 loss to control cell self-renewal and drive ATRT. We performed an unbiased epigenome-targeted screen to identify genes that cooperate with SMARCB1 and identified SIRT2 as a key regulator. Using in vitro pluripotency assays combined with in vivo single-cell RNA transcriptomics, we examined the impact of SIRT2 on differentiation of ATRT cells. We used a series of orthotopic murine models treated with SIRT2 inhibitors to examine the impact on survival and clinical applicability. We found that ATRT cells are highly dependent on SIRT2 for survival. Genetic or chemical inhibition led to decreased cell self-renewal and induction of differentiation in tumor spheres and in vivo models. We found that SIRT2 inhibition can restore gene expression programs lost because of SMARCB1 loss and reverse the differentiation block in ATRT in vivo. Finally, we showed the &lt...