由于多发性骨髓瘤的难治性，非常需要开展基础研究来扩大多发性骨髓瘤的治疗选择。组蛋白脱乙酰酶 (HDAC) 抑制剂是表观遗传调节剂，很有吸引力，但应用有限。 MicroRNA (miRNA) 也是表观遗传调节因子，是可能带来未来治疗突破的重要分子。在这项研究中，我们全面搜索了骨髓瘤细胞中被 HDAC 抑制剂改变的 miRNA。我们确定 miR-7-5p (miR-7) 是 HDAC 抑制剂下调的 miRNA。用 miR-7 转染骨髓瘤细胞系可抑制细胞增殖、诱导细胞凋亡并增强 HDAC 抑制剂帕比司他的作用。 miR-7 的表达因 c-Myc 抑制而下调，但因硼替佐米而上调。对 miR-7 靶标的全面检查发现了四个候选靶标：SLC6A9、LRRC59、EXOSC2 和 PSME3。其中，我们重点关注 PSME3，这是一种与骨髓瘤细胞蛋白酶体能力相关的癌基因。 PSME3 敲低会增加骨髓瘤细胞死亡和帕比司他敏感性。总之，被 HDAC 抑制剂下调的 miR-7 是一种靶向 PSME3 的肿瘤抑制因子。这种 miR-7 下调可能与 HDAC 抑制剂耐药性有关。此外，应考虑联合使用抗骨髓瘤药物来补充 miRNA 表达的变化。© 2024。日本血液学会。

Basic research to expand treatment options for multiple myeloma is greatly needed due to the refractory nature of the disease. Histone deacetylase (HDAC) inhibitors, which are epigenetic regulators, are attractive but have limited applications. MicroRNAs (miRNAs), which are also epigenetic regulators, are important molecules that may lead to future therapeutic breakthroughs. In this study, we comprehensively searched for miRNAs that are altered by HDAC inhibitors in myeloma cells. We identified miR-7-5p (miR-7) as a miRNA downregulated by HDAC inhibitors. Transfection of myeloma cell lines with miR-7 suppressed cell proliferation, induced apoptosis, and enhanced the effects of the HDAC inhibitor panobinostat. Expression of miR-7 was downregulated by c-Myc inhibition, but upregulated by bortezomib. Comprehensive examination of miR-7 targets revealed four candidates: SLC6A9, LRRC59, EXOSC2, and PSME3. Among these, we focused on PSME3, an oncogene involved in proteasome capacity in myeloma cells. PSME3 knockdown increases myeloma cell death and panobinostat sensitivity. In conclusion, miR-7, which is downregulated by HDAC inhibitors, is a tumor suppressor that targets PSME3. This miR-7 downregulation may be involved in HDAC inhibitor resistance. In addition, combinations of anti-myeloma drugs that complement changes in miRNA expression should be considered.© 2024. Japanese Society of Hematology.