Inhibition of hsa_circ_0003489 shifts balance from autophagy to apoptosis and sensitizes multiple myeloma cells to bortezomib via miR‐874‐3p/HDAC1 axis

Abstract

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.

Comprehensive elaboration of circular RNA in multiple myeloma

“…In parallel, circRERE was upregulated in BTZ-resistant MM samples and cells, and it positively regulated CD47 by sponging miR-152-3p, facilitating the resistance of MM to BTZ ( Fang et al, 2021 ). Recently, Tian et al ( Tian et al, 2021 ) found that silencing of circ_0003489 sensitized MM cells to BTZ in vitro and in vivo experiments. In-depth study unveiled that circ_0003489 sponged miR-874-3p and positively regulated its target protein, HDAC1, therefore attenuating the cytotoxic effects of BTZ in MM cells and reversing its inhibiting effect on autophagy ( Tian et al, 2021 ).…”

miR-874: An Important Regulator in Human Diseases

“…As shown in Table 1 , miR-874 is downregulated in at least 22 human malignancies, such as colorectal cancer (CRC) ( Huang et al, 2020a ; Yu et al, 2020 ; Que et al, 2017 ; Zhao and Dong, 2016 ; Han et al, 2016 ; Wang et al, 2021 ; Zhang et al, 2021c ), gastric cancer (GC) ( Huang et al, 2018 ; Sun et al, 2020 ; Yuan et al, 2020 ; Liu et al, 2017 ; Zhang et al, 2015 ; Jiang et al, 2014 ), hepatocellular carcinoma (HCC) ( Zhang et al, 2018b ; Jiang et al, 2017 ; Leong et al, 2017 ; Song et al, 2016 ), esophageal squamous cell carcinoma (ESCC) ( Yuan et al, 2018 ), pancreatic ductal adenocarcinoma (PDAC) ( Diao et al, 2018 ), non-small cell lung cancer (NSCLC) ( Bu et al, 2020 ; Yang et al, 2017 ; Ahmad et al, 2015 ; Kesanakurti et al, 2013 ; Wang et al, 2020b ), osteosarcoma (OS) ( Tang et al, 2018 ; Liu et al, 2020 ; Dong et al, 2016 ; Ghosh et al, 2017 ), epithelial ovarian cancer (EOC) ( Xia et al, 2018 ) cervical cancer (CC) ( Liao et al, 2018 ; Liu et al, 2021a ), retinoblastoma (RB) ( Zhang et al, 2018a ; Wang et al, 2020a ), prostate cancer (PCa) ( Pashaei et al, 2017 ) maxillary sinus squamous cell carcinoma (MSCC) ( Nohata et al, 2011 ), breast cancer (BC) ( Li et al, 2020 ; Zhang et al, 2017 ; Wang et al, 2014 ), triple-negative breast cancer (TNBC) ( Wu et al, 2020 ), rhabdomyosarcoma (RMS) ( Shang et al, 2019 ), papillary thyroid carcinoma (PTC) ( Ding et al, 2021 ), endometrial cancer ( Witek et al, 2021 ), cholangiocarcinoma ( Pan et al, 2021 ), glioma ( Li et al, 2021a ), myeloma (MM) ( Tian et al, 2021 ), head and neck squamous cell carcinoma (HNSCC) ( Nohata et al, 2013 ) and acute myeloid leukemia (AML) ( Zhang et al, 2021a ).…”

“…In AML, the DANCR/miR-874-3p/ATG16L1 axis can promote autophagy, thereby enhancing the resistance of human AML cells to Ara-C ( Zhang et al, 2021a ). In addition, knocking out circ_0003489 can upregulate miR-874-3p and inhibit HDAC1, thereby prompting MM cells to switch from autophagy to apoptosis, and reducing the growth of MM cells ( Tian et al, 2021 ).…”

“…In MM, the circ_0003489/miR-874-3p/HDAC1 axis plays a crucial role in controlling the balance of autophagy and apoptosis in MM cells. Downregulation of circ_0003489 can increase the inhibition of miR-874-3p on HDAC1, and improve the efficacy of BTZ in the treatment of MM ( Tian et al, 2021 ).…”

Roles of circRNAs in hematological malignancies

“…For example, cir-cANXA2 [74] was associated with chemoresistance of cytarabine and daunorubicin in AML. Similarly, circPAN3 [26] induced chemoresistance of adriamycin (ADM) via sponging miR-153-5p/miR-183-5p, while bortezomib (BTZ)-circ-0003489 [75] may regulate resistance in MM. Circ-0009910 triggered the activation of autophagy by sponging miR-34a-5p to promote imatinib resistance in chronic myeloid leukemia [68].…”