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Brd4, H3K27Ac, and H3K36me3 binding profiles with or without Dinaciclib in human neuroblastoma CLB-GA cells

ABSTRACT: Promoter rearrangement of the telomerase reverse transcriptase (TERT) gene juxtaposes the coding sequence to strong enhancer elements, leading to TERT overexpression and poor prognosis. TERT associated oncogenic signaling in neuroblastoma remains unclear. Gene set enrichment analysis of RNA-seq data from 498 neuroblastoma patients revealed a coordinated activation of oncogenic signaling pathways and differentially overexpressed gene signature in a subgroup of MycN non-amplified neuroblastomas with TERT overexpression. ChIP-seq analysis of human neuroblastoma cell line CLB-GA harboring TERT rearrangement uncovered genome-wide chromatin co-occupancy of Brd4 and H3K27Ac and robust enrichment of H3K36me3 in TERT and multiple TERT-associated genes. We demonstrated a critical regulatory role of Brd4 and cyclin-dependent kinases in the expression and chromatin activation. Inhibition of both with AZD5153 and dinaciclib proved most effective in tumor growth suppression of neuroblastoma cell lines, primary cells, and xenograft. Our study provides a therapeutic strategy utilizing epigenetic targeting of neuroblastoma with TERT overexpression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE133453 | GEO | 2020/05/12

REPOSITORIES: GEO

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