The CoREST complex inhibitor, corin, leads to decreased tumor growth, increased cellular differentiation and extended lifespan in atypical teratoid rhabdoid tumor xenograft models

Abstract

BackgroundAtypical teratoid rhabdoid tumor (ATRT) is the most common malignant brain tumor in infants, and more than 60% of children with ATRT die from their tumor. ATRT is associated with mutational inactivation/deletion of SMARCB1, a member of the SWI/SNF chromatin remodeling complex, suggesting that epigenetic events play a critical role in tumor development and progression. Moreover, disruption of SWI/SNF allows unopposed activity of epigenetic repressors, which contribute to tumorigenicity. We therefore explored the role of the CoREST repressor complex in ATRT. MethodsWe evaluated the effects of the bifunctional LSD1/HDAC1/2 small molecule CoREST inhibitor, corin, on ATRT tumor cell growth, apoptosis, differentiation, gene expression and chromatin accessibility. ResultsWe found that corin inhibited the growth of ATRT cells regardless of their epigenetic subgroup, and was associated with increased tumor cell apoptosis and differentiation. ATAC-seq showed increases in chromatin accessibility in corin-treated ATRT cells, with changes seen at genes associated with neuronal differentiation and synaptic function. RNA-seq confirmed increased expression of neuronal differentiation genes and decreased DNA replication/cell cycle-associated genes in ATRT cells treated with corin. Corin suppressed orthotopic ATRT tumor growth, leading to significant extension of lifespan. In addition, increased histone acetylation (H3K9ac, H3K27ac) and methylation (H3K4Me1) was seen in corin-treated ATRT orthotopic xenografts, consistent with on-target pharmacodynamics. ConclusionThe CoREST inhibitor, corin, suppresses tumor growth, induces differentiation, and promotes apoptosis in ATRT, leading to significantly increased survival of mice bearing ATRT orthotopic xenografts. Our results suggest a potential application of CoREST complex inhibitors in patients with ATRT. Key PointsO_LICoREST complex inhibition by corin leads to decreased cell growth and increased apoptosis in ATRT C_LIO_LICorin promotes chromatin accessibility and neuronal differentiation in ATRT C_LIO_LICorin inhibits tumor growth and extends lifespan in ATRT animal models C_LI Importance of the StudyLoss of function of SMARCB1 is a hallmark of ATRT which leads to dysfunction of the mammalian SWI/SNF complex and an inability to counteract epigenetic repressor complexes. The CoREST complex functions as a chromatin remodeling complex that represses neuronal differentiation genes during development. Inhibition of the CoREST complex by corin in ATRT leads to decreased tumor cell growth, induction of apoptosis and increased survival of mice bearing ATRT orthotopic xenografts. These changes are associated with increased chromatin accessibility and expression of genes associated with neuronal differentiation. Corin therefore reverses the primary block of differentiation that maintains a stem cell state in ATRT, which contributes to tumorigenesis. These studies significantly improve our understanding of how to therapeutically address the underlying epigenetic drivers of ATRT and support further development of corin for ATRT.