miR-1293, a Candidate for miRNA-Based Cancer Therapeutics, Simultaneously Targets BRD4 and the DNA Repair Pathway.
Apoptosis
/ genetics
Cell Cycle Proteins
/ genetics
Cell Line, Tumor
DNA Repair
Databases, Genetic
Gene Expression
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Gene Library
Humans
MicroRNAs
/ genetics
Neoplasms
/ genetics
RNA Interference
Transcription Factors
/ genetics
Transfection
BRD4
DNA repair
cancer
miR-1293
nucleic acid therapeutics
Journal
Molecular therapy : the journal of the American Society of Gene Therapy
ISSN: 1525-0024
Titre abrégé: Mol Ther
Pays: United States
ID NLM: 100890581
Informations de publication
Date de publication:
03 06 2020
03 06 2020
Historique:
received:
20
11
2019
revised:
04
03
2020
accepted:
02
04
2020
pubmed:
23
4
2020
medline:
3
6
2021
entrez:
23
4
2020
Statut:
ppublish
Résumé
BRD4, a member of the bromodomain and extra-terminal domain (BET) protein family, plays a role in the organization of super-enhancers and transcriptional activation of oncogenes in cancer and is recognized as a promising target for cancer therapy. microRNAs (miRNAs), endogenous small noncoding RNAs, cause mRNA degradation or inhibit protein translation of their target genes by binding to complementary sequences. miRNA mimics simultaneously targeting several tumor-promoting genes and BRD4 may be useful as therapeutic agents of tumor-suppressive miRNAs (TS-miRs) for cancer therapy. To investigate TS-miRs for the development of miRNA-based cancer therapeutics, we performed function-based screening in 10 cancer cell lines with a library containing 2,565 human miRNA mimics. Consequently, miR-1293, miR-876-3p, and miR-6571-5p were identified as TS-miRs targeting BRD4 in this screening. Notably, miR-1293 also suppressed DNA repair pathways by directly suppressing the DNA repair genes APEX1 (apurinic-apyrimidinic endonuclease 1), RPA1 (replication protein A1), and POLD4 (DNA polymerase delta 4, accessory subunit). Concurrent suppression of BRD4 and these DNA repair genes synergistically inhibited tumor cell growth in vitro. Furthermore, administration of miR-1293 suppressed in vivo tumor growth in a xenograft mouse model. These results suggest that miR-1293 is a candidate for the development of miRNA-based cancer therapeutics.
Identifiants
pubmed: 32320642
pii: S1525-0016(20)30182-9
doi: 10.1016/j.ymthe.2020.04.001
pmc: PMC7264468
pii:
doi:
Substances chimiques
BRD4 protein, human
0
Cell Cycle Proteins
0
MIRN1293 microRNA, human
0
MicroRNAs
0
Transcription Factors
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1494-1505Informations de copyright
Copyright © 2020. Published by Elsevier Inc.
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