Abstract 2084: Reprogramming the epigenome as an effective treatment option for neurofibromatosis1 associated malignant peripheral nerve sheath tumors
Authors: Mayanil Chandra S. , Khan Mariam M. , Mohanty Vineet , Kumar Raj , Xi Guifa , Ichi Shunsuke , Singh Bal Ram , Mania-Farnell Barbara , Tomita Tadanori 
Published: August 2018

Neurofibromatosis type 1 (NF1) is common, occurring in 1 in 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. It arises from a mutated and non-functional tumor suppressor gene NF1. Tumors of the peripheral nerves, called neurofibromas and of the main eye nerve, called optic glioma, are debilitating and deadly. Epigenetic mechanisms have been shown to play an important role in the progression of neurofibromas to malignant peripheral nerve sheath tumors (MPNSTs). MPNSTs with polycomb repressive complex 2 (PRC2) loss showed complete loss of trimethylation at lysine 27 of histone H3 (H3K27me3). We hypothesized that owing to the loss of this repressive complex PRC2, there is an overexpression of genes related to tumorigenesis in MPNSTs because of reciprocal gain of the activation marks such as trimethylation at lysine 4 of histone H3 (H3K4me3) and acetylation of lysine 27 of histone H3 (H3K27Ac) at their promoters. Using RT-PCR, we observed an increase in the expression of candidate oncogenes genes PAX2, FOXN4, IGF2 and TLX1 in NF1 associated MPNST cell line ST88-14 versus the normal Schwann cells and normal human fibroblasts. Western blots using purified histones revealed that there was an increase in the expression of H3K4me3, H3K9me2, H3K18Ac and H3K27Ac. Recently, aqueous extracts of Ocimum Sanctum has been used as investigational cancer preventive drug. We wanted to know the effects of extracts of O. Sanctum on MPNST cell line ST88-14. Treatment of ST88-14 cells with the hydrophilic fraction of methanolic extract of Ocimum Sanctum (OSHP-1) not only showed a dose dependent decrease in the above histone marks but also showed an increase in the expression of N-CAM 140KD, characteristic of mature Schwann cells, in addition to a significant decline in proliferation. Further evaluation of the nuclear extracts showed that OSHP-1 treatment increased the expression of HDAC2, a component of NuRD complex and decreased that of lysine acetyl transferase 7 (KAT7) in a dose dependent manner suggesting that both HDAC2 and KAT7 may be responsible for the decrease in the acetylation of H3K27Ac and therefore reversal of the tumorigenic MPNSTs to a differentiated Schwann cell phenotype. Chromatin immunoprecipitation (ChIP) data revealed H3K27Ac occupancy on candidate genes (PAX2, FOXN4, IGF2 and TLX1) promoters was reduced by OSHP-1 treatment. In conclusion, OSHP-1 reprograms the epigenome and may be an effective treatment option for NF1 associated MPNSTs.

Citation Format: Chandra S. Mayanil, Mariam M. Khan, Vineet Mohanty, Raj Kumar, Guifa Xi, Shunsuke Ichi, Bal Ram Singh, Barbara Mania-Farnell, Tadanori Tomita. Reprogramming the epigenome as an effective treatment option for neurofibromatosis1 associated malignant peripheral nerve sheath tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2084.