miR-1293, a Candidate for miRNA-Based Cancer Therapeutics, Simultaneously Targets BRD4 and the DNA Repair Pathway

Yuki Takagawa; Yasuyuki Gen; Tomoki Muramatsu; Kousuke Tanimoto; Jun Inoue; Hiroyuki Harada; Johji Inazawa

doi:10.1016/j.ymthe.2020.04.001

miR-1293, a Candidate for miRNA-Based Cancer Therapeutics, Simultaneously Targets BRD4 and the DNA Repair Pathway

Mol Ther. 2020 Jun 3;28(6):1494-1505. doi: 10.1016/j.ymthe.2020.04.001. Epub 2020 Apr 11.

Authors

Yuki Takagawa¹, Yasuyuki Gen², Tomoki Muramatsu³, Kousuke Tanimoto⁴, Jun Inoue³, Hiroyuki Harada⁵, Johji Inazawa⁶

Affiliations

¹ Department of Molecular Cytogenetics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan; Department of Oral and Maxillofacial Surgery, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
² Department of Molecular Cytogenetics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan. Electronic address: ygen.cgen@mri.tmd.ac.jp.
³ Department of Molecular Cytogenetics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
⁴ Genome Laboratory, Medical Research Institute, TMDU, Tokyo, Japan.
⁵ Department of Oral and Maxillofacial Surgery, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
⁶ Department of Molecular Cytogenetics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan; Bioresource Research Center, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan. Electronic address: johinaz.cgen@mri.tmd.ac.jp.

Abstract

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.

Keywords: BRD4; DNA repair; cancer; miR-1293; nucleic acid therapeutics.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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
Neoplasms / therapy
RNA Interference*
Transcription Factors / genetics*
Transfection

Substances

BRD4 protein, human
Cell Cycle Proteins
MIRN1293 microRNA, human
MicroRNAs
Transcription Factors