miR-1293, a Candidate for miRNA-Based Cancer Therapeutics, Simultaneously Targets BRD4 and the DNA Repair Pathway
miR-1293, a Candidate for miRNA-Based Cancer Therapeutics, Simultaneously Targets BRD4 and the DNA Repair Pathway
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DOI：
10.1016/j.ymthe.2020.04.001
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发表时间：
2020-06-03
影响因子：
12.4
通讯作者：
Inazawa, Johji
中科院分区：
文献类型：
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作者：
Takagawa, Yuki;Gen, Yasuyuki;Inazawa, Johji
BRD4是溴域和外端结构域（BET）蛋白家族的一员，在癌症中组织超增强子和癌基因的转录激活中起作用，被认为是癌症治疗的一个有希望的靶点。microRNAs （miRNAs）是内源性小非编码rna，通过与互补序列结合导致mRNA降解或抑制靶基因的蛋白质翻译。同时靶向几种肿瘤促进基因和BRD4的miRNA模拟物可能作为肿瘤抑制miRNAs （TS-miRs）的治疗剂用于癌症治疗。为了研究TS-miRs在开发基于miRNA的癌症疗法中的作用，我们在10个癌细胞系中进行了基于功能的筛选，其中包含2565个人类miRNA模拟物。因此，在本次筛选中，miR-1293、miR-876-3p和miR-6571-5p被鉴定为靶向BRD4的ts - mir。值得注意的是，miR-1293还通过直接抑制DNA修复基因APEX1（无尿嘧啶-无嘧啶内切酶1）、RPA1（复制蛋白A1）和POLD4 （DNA聚合酶δ 4，辅助亚基）来抑制DNA修复途径。同时抑制BRD4和这些DNA修复基因在体外协同抑制肿瘤细胞生长。此外，在异种移植小鼠模型中，miR-1293抑制了体内肿瘤的生长。这些结果表明，miR-1293是开发基于mirna的癌症治疗方法的候选者。
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.