DDX56 transcriptionally activates MIST1 to facilitate tumorigenesis of HCC through PTEN-AKT signaling

Abstract

Rationale : Hepatocellular carcinoma (HCC) is a primary malignancy of the liver that is the leading cause of cancer-related mortality worldwide. However, genetic alterations and mechanisms underlying HCC development remain unclear. Methods: Tissue specimens were used to evaluate the expression of DEAD-Box 56 (DDX56) to determine its prognostic value. Colony formation, CCK8, and EdU-labelling assays were performed to assess the effects of DDX56 on HCC proliferation. The in vivo role of DDX56 was evaluated using mouse orthotopic liver xenograft and subcutaneous xenograft tumor models. Dual-luciferase reporter, chromatin immunoprecipitation, and electrophoretic mobility shift assays were performed to examine the effect of DDX56 on the MIST1 promoter. Results: DDX56 expression in HCC tissues was elevated and this increase was strongly correlated with poor prognoses for HCC patients. Functionally, DDX56 promoted HCC cell proliferation both in vitro and in vivo , while mechanistically interacting with MECOM to promote HCC proliferation by mono-methylating H3K9 (H3K9me1) on the MIST1 promoter, leading to enhanced MIST1 transcription and subsequent regulation of the PTEN/AKT signaling pathway, which promotes HCC proliferation. More importantly, the PTEN agonist, Oroxin B (OB), blocked the DDX56-mediated PTEN-AKT signaling pathway, suggesting that treating HCC patients with OB may be beneficial as a therapeutic intervention. Furthermore, we observed that ZEB1 bound to DDX56 and transcriptionally activated DDX56, leading to HCC tumorigenesis. Conclusions: Our results indicated that the ZEB1-DDX56-MIST1 axis played a vital role in sustaining the malignant progression of HCC and identified DDX56 as a potential therapeutic target in HCC tumorigenesis.

High expression of TBRG4 in relation to unfavorable outcome and cell ferroptosis in hepatocellular carcinoma

“…In the previous bioinformatics prediction, TBRG4 showed a strong correlation with DDX56. Studies have shown that DDX56 can inhibit the proliferation and migration of HCC cells through the PTEN/p-AKT signaling pathway [ 18 ]. We speculate that TBRG4 may participate in the AKT signaling pathway through DDX56.…”

“…DDX56 is a component of 65S ribosomal precursor particles that regulate various RNA metabolism processes, including transcription [ 26 ]. Research has shown that DDX56 interacts with MECOM to promote the growth of HCC cells through the PTEN/p-AKT signaling pathway [ 18 ]. Our study found that downregulating TBRG4 can reduce the expression of DDX56/p-AKT.…”

Hairy gene homolog increases nasopharyngeal carcinoma cell stemness by upregulating Bmi-1

“…A previous study revealed that Bmi-1 transcriptionally repressed the tumor suppressor phosphatase and tensin homolog (PTEN), thereby activating the phosphoinositide 3-kinase (PI3K)/AKT pathway, inducing the EMT and promoting the invasion and metastasis of NPC cells [23]. The suppression of PTEN has been shown to activate the PI3K/AKT/ glycogen synthase kinase 3β pathway in various kinds of cancer cells, thus greatly promoting their proliferation and stemness [71][72][73][74][75][76][77]. These data suggest that Bmi-1 may enhance the proliferation and stemness of NPC cells by inducing PTEN/PI3K/AKT signaling, although further investigation is needed to confirm this.…”

Circular RNAs in Epithelial Ovarian Cancer: From Biomarkers to Therapeutic Targets

“…CircRHOBTB3 (circ_0007444) was reported to inhibit EOC progression by serving as a ceRNA to facilitate PTEN expression [ 110 , 111 ]. PTEN is a critical tumor suppressor in a variety of cancers, including EOC [ 202 , 203 , 204 , 205 ]. Wu et al [ 111 ] showed that circ_0007444 was markedly decreased in tumor samples, as compared with normal tissues.…”