Circular RNA circ-CDYL sponges miR-1180 to elevate yes-associated protein in multiple myeloma

Abstract

<jats:p> The covalently closed circular RNA has recently been proposed as a pivotal player in tumorigenesis. In the current study, we found that circ-CDYL was notably elevated in multiple myeloma tissue and plasma samples and had good diagnostic and prognostic efficacy. Functional assays showed that circ-CDYL enhanced the viability and DNA synthesis of multiple myeloma cells and inhibited apoptosis. Mechanically, cytoplasmic circ-CDYL was co-localized with miR-1180, and circ-CDYL absorbed miR-1180 to upregulate yes-associated protein (YAP), thereby facilitating multiple myeloma progression. Importantly, we further confirmed the existence of this circ-CDYL/miR-1180/YAP regulatory axis in vivo by using the xenograft tumor model. Taken together, our data demonstrate that circ-CDYL is novel promoter of multiple myeloma, and targeting circ-CDYL and its associated network implicates the therapeutic possibility for multiple myeloma patients. </jats:p><jats:sec><jats:title>Impact statement</jats:title><jats:p> Multiple myeloma (MM) is an extremely complex and heterogeneous disease, and its pathogenesis is poorly understood. Here, we described an important MM-related circular RNA (circRNA), circ-CDYL. It was remarkably increased in both MM cells and plasma. Depletion of circ-CDYL evidently stunted MM growth. Circ-CDYL could absorb miR-1180 and alleviated the repression of miR-1180 on YAP, leading to increased YAP expression, ultimately triggering MM uncontrolled growth. Therefore, our findings advance the understanding of MM pathogenesis, and also raise the possibility of considering circ-CDYL as a potential therapeutic intervention for MM. </jats:p></jats:sec>

Circular RNAs: Emerging Role in Cancer Diagnostics and Therapeutics

“…Circ-CDYL facilitated MM growth by sponging miR-1180 and increasing the expression of its target YAP (Chen F. et al, 2020). Downregulation of circ-CDYL induces apoptosis by downregulating YAP (Chen F. et al, 2020).…”

The functions and clinical significance of circRNAs in hematological malignancies

“…CircCDYL was demonstrated to enhance the autophagic level in breast cancer through miR-1275/ATG7/ULK1 axis [63]. It is worth noting that upregulated levels of circCDYL were also detected in MCL and MM and might serve as potential biomarkers for diagnosis [34,35]. However, the involvement of circCDYL in the autophagy of hematological malignancies still needs further investigation.…”

“…Knockdown of circCDYL could inhibit DNA synthesis rate and cell activities to stunt MM progression. Silencing circCDYL decreased the expression of YAP, the key effector of Hippo signaling, and upregulated miR-1180 in MM xenograft model [35,36]. Circ_0000190, downregulated in the tissues and plasma of MM patients, restrained the proliferation of MM cells through modulating the miR-767-5p/MAPK4 axis [37].…”

“…Augmented expression of circ-APC inhibited the growth of diffuse large B-cell lymphoma (DLBCL) cells in vitro and in vivo by recruiting TET1 to the promoter of APC, subsequently resulted in the activation of canonical Wnt/β-catenin signaling pathway [33]. Remarkable overexpression of circ-CDYL was detected in the plasma of mantle cell lymphoma (MCL) and multiple myeloma (MM) patients [34,35]. Knockdown of circCDYL could inhibit DNA synthesis rate and cell activities to stunt MM progression.…”

“…Transcripts of circRNAs could be packaged into viral vectors or oligonucleotide and then delivered to target cells to mediate their therapeutic effects [ 96 ]. Inhibiting the expression of specific circRNA could enhance the protective function of the relevant miRNAs in inhibiting oncogenes, such as XIAP, β-catenin, GSK3β and YAP [ 24 , 31 , 35 , 43 ]. Recently, the CRISPR/Cas9-mediated genetic engineering technology provides a robust tool for circRNAs investigation.…”