The CoREST complex inhibitor, corin, decreases tumor growth, increases cellular differentiation and extends lifespan in ATRT xenograft models

Rezumat

Abstract Background Atypical teratoid rhabdoid tumor (ATRT) is the most common malignant brain tumor in infants. ATRT is associated with inactivation/deletion of SMARCB1, a member of the SWI/SNF chromatin remodeling complex. SMARCB1 loss contributes to tumorigenicity by compromising SWI/SNF activity at specific loci associated with the CoREST repressor complex, which regulates transcription at critical gene promoters and enhancers. We therefore explored the role of the CoREST repressor complex in ATRT. Methods We 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. Results Corin inhibited the growth of ATRT cells regardless of their epigenetic subgroup. Corin caused increased tumor cell apoptosis and differentiation. ATAC-seq showed increased 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 in ATRT cells treated with corin. Knockdown of RCOR2 phenocopied the effects of corin and desensitized the cells to the drug, confirming corin specificity to the CoREST complex. Corin suppressed orthotopic ATRT tumor growth, leading to significant extension of lifespan in ATRT mouse models. Corin caused increased histone acetylation (H3K9ac) and methylation (H3K4Me1) in ATRT orthotopic xenografts, consistent with on-target pharmacodynamics. Conclusions The CoREST inhibitor, corin, suppressed tumor growth, induced differentiation, and promoted 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.