NFM-10. TARGETING NuRD AND KAT7 FOR EPIGENOME MODIFICATION IN NEUROFIBROMATOSIS1 ASSOCIATED MALIGNANT PERIPHERAL NERVE SHEATH TUMORS

摘要

Neurofibromatosis type 1 (NF1) is common, occurring in 1/3000 live births, and results in skin pigmentation and the growth of tumors along nerves in the skin, brain, and other parts of the body. Loss of polycomb repressive complex 2 (PRC2) has been implicated in the tumorigenesis of Schwann cells (SCs) in malignant peripheral nerve sheath tumors (MPNSTs). In the absence of PRC2, the H3K27me repressive marks are absent and thus the SCs can re-enter the cell cycle and form tumors. In the absence of PRC2, nucleosome remodeling deacetylase (NuRD) chromatin silencing complex, by itself cannot takes over its function. To compensate for the loss of PRC2 complex, there must be a decrease in activating histone marks, H3K27Ac and H3K4me3, by a reciprocal increase in HDAC2 expression and the decrease in H3K4 methylation. Using a systems biology approach as a part of the combination therapy, we have identified a novel naturally occurring multi-target cocktail in the methanolic extracts from the hydrophilic fraction of Ocimum Sanctum leaves (OSHP-1) as potential treatment option for MPNSTs. Here we show that OSHP-1 (i) increased the expression of HDAC2 (a component of NuRD), and decreased the expression of lysine acetyl transferase 7 (KAT7); (ii) altered FRα signaling and disrupted the DNA replication complex comprising of FRα-NuRD-PCNA-CAF-1; (iii) reversed the expression of certain actively transcribed genes PAX2, FOXN4, IGF2 and TLX1 in NF1-MPNST cells; (iv) increased the expression of a Schwann cell differentiation marker NCAM-140 KD. Thus, NuRD and KAT7 in NF1-MPNST can be potential therapeutic targets.