Hotspots of Aberrant Enhancer Activity in Fibrolamellar Carcinoma Reveal Candidate Oncogenic Pathways and Therapeutic Vulnerabilities.
Adolescent
CA-125 Antigen
/ genetics
Carcinogenesis
/ pathology
Carcinoma, Hepatocellular
/ genetics
Cell Proliferation
/ genetics
Chromatin
/ genetics
Computational Biology
/ methods
Enhancer Elements, Genetic
/ genetics
Gene Expression Regulation, Neoplastic
/ genetics
Humans
Liver
/ pathology
Liver Neoplasms
/ pathology
MAP Kinase Signaling System
/ genetics
Membrane Proteins
/ genetics
Monocarboxylic Acid Transporters
/ genetics
Oncogenes
/ genetics
Sequence Analysis, DNA
/ methods
Signal Transduction
/ genetics
MAPK
cancer
drug resistance
enhancers
fibrolamellar carcinoma
genomics
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
14 04 2020
14 04 2020
Historique:
received:
23
09
2019
revised:
11
02
2020
accepted:
23
03
2020
entrez:
16
4
2020
pubmed:
16
4
2020
medline:
28
4
2021
Statut:
ppublish
Résumé
Fibrolamellar carcinoma (FLC) is a rare, therapeutically intractable liver cancer that disproportionately affects youth. Although FLC tumors exhibit a distinct gene expression profile, the chromatin regulatory landscape and the genes most critical for tumor cell survival remain unclear. Here, we use chromatin run-on sequencing to discover ∼7,000 enhancers and 141 enhancer hotspots activated in FLC relative to nonmalignant liver. Bioinformatic analyses reveal aberrant ERK/MEK signaling and candidate master transcriptional regulators. We also define the genes most strongly associated with hotspots of FLC enhancer activity, including CA12 and SLC16A14. Treatment of FLC cell models with inhibitors of CA12 or SLC16A14 independently reduce cell viability and/or significantly enhance the effect of the MEK inhibitor cobimetinib. These findings highlight molecular targets for drug development, as well as drug combination approaches.
Identifiants
pubmed: 32294439
pii: S2211-1247(20)30399-5
doi: 10.1016/j.celrep.2020.03.073
pmc: PMC7474926
mid: NIHMS1612318
pii:
doi:
Substances chimiques
CA-125 Antigen
0
Chromatin
0
MUC16 protein, human
0
Membrane Proteins
0
Monocarboxylic Acid Transporters
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
107509Subventions
Organisme : NIDDK NIH HHS
ID : R01 DK105542
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK119186
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK119192
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM008719
Pays : United States
Informations de copyright
Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Interests The authors declare no competing interests.
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