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Inhibition of hsa_circ_0003489 shifts balance from autophagy to apoptosis and sensitizes multiple myeloma cells to bortezomib via miR‐874‐3p/HDAC1 axis
Author(s) -
Tian FaQing,
Chen ZiRen,
Zhu Wei,
Tang MeiQin,
Li JuHeng,
Zhang XuChang,
Jiang Jian,
Cheng XiaoHui
Publication year - 2021
Publication title -
the journal of gene medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.689
H-Index - 91
eISSN - 1521-2254
pISSN - 1099-498X
DOI - 10.1002/jgm.3329
Subject(s) - apoptosis , viability assay , autophagy , chemistry , bortezomib , microbiology and biotechnology , cell growth , hdac1 , flow cytometry , gene silencing , cancer research , biology , histone deacetylase , histone , biochemistry , immunology , multiple myeloma , gene
Background Circular RNAs (circRNAs) crucially regulate tumor progression. In this study, we examined the functional roles and mechanisms of hsa_circ_0003489 in multiple myeloma (MM). Methods Upon altering the expressions of hsa_circ_0003489, miR‐874‐3p, and/or histone deacetylase 1 (HDAC1) in MM1.R cells and treating them with bortezomib (BTZ), cell viability was examined by CCK‐8 assay; cell proliferation by Ki‐67 immunofluorescence; apoptosis by TUNEL staining, flow cytometry, and western blot; and autophagy by electron microscopy and western blot. The interaction between hsa_circ_0003489 and miR‐874‐3p as well as that between miR‐874‐3p and HDAC1 was examined by expressional analysis, dual luciferase reporter assay, and RNA immunoprecipitation. The in vivo impacts of hsa_circ_0003489 on MM growth and sensitivity to BTZ were examined using an MM xenograft mouse model. Results Knocking down hsa_circ_0003489 significantly inhibited the viability, cell proliferation, and autophagy, while promoting the apoptosis of MM cells in vitro and MM xenograft in vivo . Suppressing hsa_circ_0003489 also further boosted the cytotoxic effects of BTZ in MM cells and reversed its promoting effect on autophagy. Mechanically, hsa_circ_0003489 acted as a sponge of miR‐874‐3p and positively regulated the expression of miR‐874‐3p target, HDAC1. MiR‐874‐3p and HDAC1 essentially mediated the effects of hsa_circ_0003489 on cell viability, proliferation, apoptosis, and autophagy. Conclusion The hsa_circ_0003489/miR‐874‐3p/HDAC1 axis critically regulates the balance between apoptosis and autophagy. Silencing hsa_circ_0003489 sensitizes MM cells to BTZ by inhibiting autophagy and thus may boost the therapeutic effects of BTZ.