A C19MC-LIN28A-MYCN oncogenic circuit driven by hijacked super-enhancers is a distinct therapeutic vulnerability in ETMRs: A lethal brain tumor

Autor: Irtisha Singh, Stephen C. Mack, Dalia Barsyte-Lovejoy, Sarah Leary, Alyssa Reddy, Daniel Catchpoole, Yin Wang, Patrick Sin-Chan, Tannu Suwal, Cynthia Hawkins, Jean M. Mulcahy Levy, Jennifer A. Chan, Tai Tong Wong, Jean Michaud, Iqra Mumal, Charles Y. Lin, Timothy E. Van Meter, Eugene Hwang, Maryam Fouladi, Xiao-Nan Li, Dean Popovski, Palma Solano-Paez, Luca Massimi, Eloy Rivas, Hideo Nakamura, Richard Grundy, Ben Ho, Mei Lu, Ramya Ramanujachar, Peter B. Dirks, Alvaro Lassaletta, Lucie Lafay-Cousin, Sheila K. Singh, Eric Bouffet, Paul Guilhamon, Young Shin Ra, G. Yancey Gillespie, Michael D. Taylor, Claudia L. Kleinman, Nalin Gupta, Benjamin Ellezam, Nada Jabado, Annie Huang, Jeremy N. Rich, Yuchen Du, Jonathon Torchia, Holly Lindsay, Neilket Patel, Xiaolian Fan, Jordan R. Hansford, Lindsey M. Hoffman, Seung-Ki Kim, Jason Fangusaro, Donna L. Johnston
Přispěvatelé: Canadian Institutes of Health Research
Rok vydání: 2019
Předmět:
0301 basic medicine
Cancer Research
LIN28A
Settore MED/27 - NEUROCHIRURGIA
Gene regulatory network
Cell Transformation
Epigenesis
Genetic
0302 clinical medicine
Super-enhancer
Cell-cycleepigenetics
Models
Neoplasms
MYCN
therapeutics
Gene Regulatory Networks
Cancer
Regulation of gene expression
N-Myc Proto-Oncogene Protein
Tumor
microRNA
Brain Neoplasms
Cell Cycle
RNA-Binding Proteins
Cell cycle
Neoplasms
Germ Cell and Embryonal
C19MC
3. Good health
Cell Transformation
Neoplastic
Enhancer Elements
Genetic
Oncology
5.1 Pharmaceuticals
030220 oncology & carcinogenesis
Chromosomes
Human
Pair 2
Multigene Family
Pair 2
Development of treatments and therapeutic interventions
brain tumor
Human
Biotechnology
Enhancer Elements
DNA Copy Number Variations
Oncology and Carcinogenesis
Therapeutics
Biology
Models
Biological
Brain tumors
Chromosomes
03 medical and health sciences
Rare Diseases
Genetic
super-enhancer
Biomarkers
Tumor
Genetics
Humans
Genetic Predisposition to Disease
Epigenetics
Oncology & Carcinogenesis
neoplasms
Genetic Association Studies
Neoplastic
Pair 19
epigenetics
Neurosciences
Cell Biology
Oncogenes
Biological
Bromodomain
ETMR
MicroRNAs
030104 developmental biology
Gene Expression Regulation
cell-cycle
Cancer research
Germ Cell and Embryonal
Chromosomes
Human
Pair 19
Biomarkers
Epigenesis
Zdroj: Cancer cell, vol 36, iss 1
Digital.CSIC. Repositorio Institucional del CSIC
instname
ISSN: 1535-6108
1878-3686
Popis: Embryonal tumors with multilayered rosettes (ETMRs) are highly lethal infant brain cancers with characteristic amplification of Chr19q13.41 miRNA cluster (C19MC) and enrichment of pluripotency factor LIN28A. Here we investigated C19MC oncogenic mechanisms and discovered a C19MC-LIN28A-MYCN circuit fueled by multiple complex regulatory loops including an MYCN core transcriptional network and super-enhancers resulting from long-range MYCN DNA interactions and C19MC gene fusions. Our data show that this powerful oncogenic circuit, which entraps an early neural lineage network, is potently abrogated by bromodomain inhibitor JQ1, leading to ETMR cell death.
This project was funded by a Canadian Institutes of Health Research (CIHR) grant no. 137011 and b.r.a.i.n. child to A.H. T.S. is a CIHR Scholar.
Databáze: OpenAIRE
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