The CoREST complex is a therapeutic vulnerability in malignant peripheral nerve sheath tumors (ATAC-Seq)
Malignant peripheral nerve sheath tumor (MPNST) is a highly aggressive sarcoma that may be seen in patients with neurofibromatosis type 1 (NF1) or occur sporadically.  While surgery is the primary treatment for localized MPNST with a 61.9% overall survival rate, metastatic disease is often fatal due to resistance to systemic therapies which underscores the urgent need for effective treatments. MPNSTs frequently harbor inactivating driver mutations in the PRC2 epigenetic repressor complex suggesting epigenetic therapies may represent a specific vulnerability in these tumors. Here, we investigate the role of the LSD1-HDAC1-CoREST (LHC) repressor complex in mediating MPNST tumor growth and progression. Our findings demonstrate that the LHC small molecule inhibitor, corin, induces apoptosis and significantly inhibits proliferation in MPNST cells. Transcriptomic analysis of corin-treated MPNST cells demonstrates specific increases in genes associated with axonogenesis and neuronal differentiation as well as altered extracellular matrix; additionally, corin treatment is shown to inhibit MPNST invasion in vitro. These results underscore the critical role of the LHC complex in facilitating MPNST growth and progression and suggest that targeting the LHC complex represents a promising therapeutic approach for this aggressive malignancy. Overall design: 100,000 cells were seeded and treated with 1 µM Corin, HDACi, or DMSO. DNA was extracted, tagmented, purified, and adapter ligated using the ATAC-seq Kit (53150) according to the manufacturer's instructions (Active Motif). Sequencing was done by Azenta Life Sciences and reads were trimmed using the fastp command in fastp v.0.23.4. Reads were aligned with GRCh38 reference genome using bowtie2 v.2.4.2. Sam files were filtered to retain the mapped reads only and converted to BAM files using Samtools v.1.12. Bed and Bedgraph files were created using Bedtools v.2.31.0. Peaks were called using Macs2 v.2.2.7.1 with the nomodel, and nolambda options.