Arresting of miR-186 and releasing of H19 by DDX43 facilitate tumorigenesis and CML progression

Abstract

Cancer-testis (CT) antigens, rarely in normal tissues except testis, are expressed in many tumor types. In recent years, DDX43 has been shown to be expressed in several malignancies. However, the role of DDX43 during tumorigenesis is not well established. In the present study, we explored the function of DDX43 in chronic myeloid leukemia (CML). We found that DDX43 overexpression in CML cell lines enhanced survival and colony formation, inhibited cell apoptosis, promoted tumorigenesis, and CML progression. In contrast, silencing of DDX43 inhibited cell survival and tumorigenesis. Upregulated H19 and downregulated miR-186 were identified in DDX43-transfected cells. Furthermore, we demonstrated that miR-186 targeted DDX43, and overexpressed miR-186 increased apoptosis and decreased cell survival. We also showed that DDX43 regulated the expression of H19 through demethylation and silencing H19 inhibited cell survival. Taken together, these results indicate that DDX43 provides critical support to the progression of CML by enhancing cell survival, colony formation, and inhibiting cell apoptosis, thereby implicating DDX43 as a potential therapeutic target in CML.

Establishment and molecular characterization of decitabine‐resistant K562 cells

“…11,21 Therefore, it is important to illuminate the resistance mechanism and to overcome H19 is a long chain non-coding RNA with length of 2.3 kb. 20 Among AML, H19 overexpression correlated with poor chemotherapy response and shorter overall survival 36 Taken together, we deduced that H19 may play a role in drug resistance during leukemogenesis. [31][32][33][34] Our previous study revealed that H19 expression level, associated with its promoter methylation status, was significantly upregulated in CML patients involving in disease progression.…”

“…26 DDX43 provided critical support to the progression of CML by enhancing cell survival and colony formation, and inhibiting cell apoptosis in vitro and in vivo. 20 Moreover, DAC treatment in AML cell lines derepressed cancer/testis antigens localized on the X-chromosome readily and transiently, which implied long-term use of demethylated drugs may lead to genomic instability. 27 Besides, DDX43 could possibly serve as a new potential therapeutic target for recurrent colorectal cancer patients with chemoresistance.…”

“…20 Also, miR-186 was found to target DDX43, and miR-186 was downregulated in DDX43-transfected cells. 20 Also, miR-186 was found to target DDX43, and miR-186 was downregulated in DDX43-transfected cells.…”

“…Our previous study had reported that overexpression of DDX43 in K562 cell line upregulated H19 through demethylation. 20 Also, miR-186 was found to target DDX43, and miR-186 was downregulated in DDX43-transfected cells. 20 Here, the density of H19 and DDX43 methylation was greatly decreased in K562/DAC cells ( Figure 3A and B).…”

“…Drug-resistant cell line models provide us with valuable in-vitro tools in clarifying the mechanisms underlying clinical anticancer drug resistance. 26 DDX43 provided critical support to the progression of CML by enhancing cell survival and colony formation, and inhibiting cell apoptosis in vitro and in vivo 20. Furthermore, cell line models with acquired resistance play an additional and important role in discovering the action mechanism of new, developmental anticancer agents 22.…”