Increased Efficacy of Histone Methyltransferase G9a Inhibitors Against MYCN-Amplified Neuroblastoma.

Frontiers in Oncology
Jacob BellamyKarim Malik

Abstract

Targeted inhibition of proteins modulating epigenetic changes is an increasingly important priority in cancer therapeutics, and many small molecule inhibitors are currently being developed. In the case of neuroblastoma (NB), a pediatric solid tumor with a paucity of intragenic mutations, epigenetic deregulation may be especially important. In this study we validate the histone methyltransferase G9a/EHMT2 as being associated with indicators of poor prognosis in NB. Immunological analysis of G9a protein shows it to be more highly expressed in NB cell-lines with MYCN amplification, which is a primary determinant of dismal outcome in NB patients. Furthermore, G9a protein in primary tumors is expressed at higher levels in poorly differentiated/undifferentiated NB, and correlates with high EZH2 expression, a known co-operative oncoprotein in NB. Our functional analyses demonstrate that siRNA-mediated G9a depletion inhibits cell growth in all NB cell lines, but, strikingly, only triggers apoptosis in NB cells with MYCN amplification, suggesting a synthetic lethal relationship between G9a and MYCN. This pattern of sensitivity is also evident when using small molecule inhibitors of G9a, UNC0638, and UNC0642. The increased efficacy of G9...Continue Reading

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Citations

Jan 7, 2021·Cancer Metastasis Reviews·Irfete S Fetahu, Sabine Taschner-Mandl
Feb 23, 2021·Frontiers in Oncology·Ruochen LiuHongjuan Cui

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Datasets Mentioned

BETA
PRJEB35417
GSE62564

Methods Mentioned

BETA
transfection
protein assay
PCR
fluorescence activated cell sorting
RNA-seq
genetic interference

Key Resources (RRID) Mentioned

CVCL_9812
AB_2792982
AB_777102
AB_831602
AB_2070042
AB_796155
AB_470239
AB_449854
AB_262011
AB_2687583

Software Mentioned

R2 Genomics Analysis and Visualization Platform
DESEQ2
SeqMonk
Gene Signature Enrichment Analysis ( GSEA )
GSEA
TopHat2

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