Epigenetic targeting of tert-associated gene expression signature in human neuroblastoma with tert overexpression.

EPIGENETIC TARGETING OF TERT-ASSOCIATED GENE EXPRESSION SIGNATURE IN HUMAN NEUROBLASTOMA WITH TERT OVEREXPRESSION. Cancer Res. 2020 Jan 03;: Authors: Huang M, Zeki J, Sumarsono N, Coles GL, Taylor JS, Danzer E, Bruzoni M, Hazard FK, Lacayo NJ, Sakamoto KM, Dunn JCY, Spunt SL, Chiu B Abstract Neuroblastoma is a deadly pediatric solid tumor with infrequent recurrent somatic mutations. Particularly, the pathophysiology of tumors without MYCN amplification remains poorly defined. Utilizing an unbiased approach, we performed gene set enrichment analysis of RNA-seq data from 498 neuroblastoma patients and revealed a differentially overexpressed gene signature in MYCN non-amplified neuroblastomas with telomerase reverse transcriptase (TERT) gene overexpression and coordinated activation of oncogenic signaling pathways, including E2Fs, Wnt, Myc, and the DNA repair pathway. Promoter rearrangement of the TERT gene juxtaposes the coding sequence to strong enhancer elements, leading to TERT overexpression and poor prognosis in neuroblastoma, but TERT-associated oncogenic signaling remains unclear. ChIP-seq analysis of the human CLB-GA neuroblastoma cells 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. Brd4 and cyclin-dependent kinases (CDKs) had critical regulatory roles in the expression and chromatin activation of TERT an...
Source: Cell Research - Category: Cytology Authors: Tags: Cancer Res Source Type: research