Increased efficacy of histone methyltransferase G9a inhibitors against MYCN-amplified Neuroblastoma

Abstract

11Targeted inhibition of proteins modulating epigenetic changes is an increasingly important priority in 12 cancer therapeutics, and many small molecule inhibitors are currently being developed. In the case of 13 neuroblastoma (NB), a paediatric solid tumour with a paucity of intragenic mutations, epigenetic 14 deregulation may be especially important. In this study we validate the histone methyltransferase 15 G9a/EHMT2 as being associated with indicators of poor prognosis in NB. Immunological analysis of 16G9a protein shows it to be more highly expressed in NB cell-lines with MYCN amplification, which 17 is a primary determinant of dismal outcome in NB patients. Furthermore, G9a protein in primary 18 tumours is expressed at higher levels in poorly differentiated/undifferentiated NB, and correlates with 19 high EZH2 expression, a known co-operative oncoprotein in NB. Our functional analyses 20 demonstrate that siRNA-mediated G9a depletion inhibits cell growth in all NB cell lines, but, 21 strikingly, only triggers apoptosis in NB cells with MYCN amplification, suggesting a synthetic lethal

Determination of long non‑coding RNAs associated with EZH2 in neuroblastoma by RIP‑seq, RNA‑seq and ChIP‑seq

“…Transcriptome sequencing has demonstrated that neurotrophic receptor tyrosine kinase 1 may be a target of EZH2. Chen et al ( 31 ) reported that the MYCN gene binds to the EZH2 promoter, directly promoting EZH2 expression and EZH2 inhibition of neuronal differentiation in a PRC2-dependent manner ( 33 ). Tsubota et al ( 34 ) demonstrated that EZH2 inhibitors significantly repress the growth of tyrosine hydroxylase-MYCN NB mice, and that MYCN and PRC2 targets are positively correlated in NB.…”