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

Zhou，Hongzhong1,8; Du，Yiqun1,8; Wei，Xiafei2; Song，Chunli3; Song，Jianning1,6; Xu，Nanson4; Huang，Weihong5; Chen，Lichan1,6; Yao，Fuwen1; Du，Duanming7; Qiu，Chuanghua1; Zhong，Lihong1; Liu，Yuchen1; Gu，Dayong1; Wang，Jin1; Xu，Yong1

2022

10.7150/thno.72471

Theranostics   Impact Factor & Quartile

1838-7640

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.

DEAD-Box 56 Hepatocellular carcinoma Proliferation Transcription Zinc finger E-box binding homeobox 1

English

Others

China Postdoctoral Science Foundation[2020M682910];Basic and Applied Basic Research Foundation of Guangdong Province[2021-A1515110823];Basic and Applied Basic Research Foundation of Guangdong Province[2021A1515110931];China Postdoctoral Science Foundation[2022T150440];National Natural Science Foundation of China[81702088];National Natural Science Foundation of China[81972867];

2-s2.0-85137864831

Scopus

1.Department of Laboratory Medicine,Shenzhen Institute of Translational Medicine,The First Affiliated Hospital of Shenzhen University,Shenzhen Second People's Hospital,Shenzhen University,Shenzhen,China
2.Institute for Hepatology,National Clinical Research Center for Infectious Disease,Shenzhen Third People's Hospital,Southern University of Science and Technology,Shenzhen,China
3.Clinical Laboratory Medicine Center,Shenzhen Hospital,Southern Medical University,Shenzhen,China
4.Sun Yat-sen University Cancer Center,State Key Laboratory of Oncology in South China,Collaborative Innovation Center for Cancer Medicine,China
5.Department of Pathology,Guangdong Provincial People's Hospital,Guangdong Academy of Medical Sciences,China
6.Guangzhou Medical University,Guangzhou,China
7.Department of Interventional Therapy,The First Affiliated Hospital of Shenzhen University,Health Science Center,Shenzhen Second People's Hospital,Shenzhen,China
8.Shenzhen Institute of Advanced Technology,Chinese Academy of Sciences,Shenzhen,China

Zhou，Hongzhong,Du，Yiqun,Wei，Xiafei,et al. DDX56 transcriptionally activates MIST1 to facilitate tumorigenesis of HCC through PTEN-AKT signaling[J]. Theranostics,2022,12(15):6069-6087.

Zhou，Hongzhong.,Du，Yiqun.,Wei，Xiafei.,Song，Chunli.,Song，Jianning.,...&Xu，Yong.(2022).DDX56 transcriptionally activates MIST1 to facilitate tumorigenesis of HCC through PTEN-AKT signaling.Theranostics,12(15),6069-6087.

Zhou，Hongzhong,et al."DDX56 transcriptionally activates MIST1 to facilitate tumorigenesis of HCC through PTEN-AKT signaling".Theranostics 12.15(2022):6069-6087.