Hepatic ARID3A facilitates liver cancer malignancy by cooperating with CEP131 to regulate an embryonic stem cell-like gene signature

Mengting Shen; Shengli Li; Yiming Zhao; Yizhe Liu; Zhen Liu; Lin Huan; Yejun Qiao; Lu Wang; Leng Han; Zhiao Chen; Xianghuo He

doi:10.1038/s41419-022-05187-9

Hepatic ARID3A facilitates liver cancer malignancy by cooperating with CEP131 to regulate an embryonic stem cell-like gene signature

Cell Death Dis. 2022 Aug 25;13(8):732. doi: 10.1038/s41419-022-05187-9.

Authors

Mengting Shen^#¹, Shengli Li^#², Yiming Zhao^#³, Yizhe Liu¹, Zhen Liu¹, Lin Huan¹, Yejun Qiao¹, Lu Wang⁴, Leng Han⁵, Zhiao Chen^{6

7

8}, Xianghuo He^{9

10

11}

Affiliations

¹ Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
² Precision Research Center for Refractory Diseases, Institute for Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201620, China.
³ Department of Hepatic Surgery, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, China.
⁴ Department of Hepatic Surgery, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, China. wangluzl@fudan.edu.cn.
⁵ Center for Epigenetics and Disease Prevention, Institute of Biosciences and Technology, Texas A&M University, Houston, TX, 77030, USA. leng.han@tamu.edu.
⁶ Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China. zachen@fudan.edu.cn.
⁷ Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, China. zachen@fudan.edu.cn.
⁸ Shanghai Key Laboratory of Radiation Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, China. zachen@fudan.edu.cn.
⁹ Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China. xhhe@fudan.edu.cn.
¹⁰ Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, China. xhhe@fudan.edu.cn.
¹¹ Shanghai Key Laboratory of Radiation Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, China. xhhe@fudan.edu.cn.

^# Contributed equally.

Abstract

Liver cancer stemness refers to the stem cell-like phenotype of hepatocarcinoma cells and is closely related to a high degree of tumour malignancy. Here, we identified AT-rich interacting domain 3A (ARID3A) as one of the most upregulated stemness-related transcription factors in liver cancer by an in vitro functional screen. ARID3A can promote liver cancer cell viability and metastasis both in vitro and in vivo. Mechanistically, ARID3A interacts with CEP131 and transcriptionally activates KDM3A by co-occupying its promoter element, further upregulating the expression of downstream embryonic stem (ES) signature genes via demethylation of H3K9me2. ARID3A and CEP131 promote an ES cell gene signature through activation of KDM3A and contribute to the poor prognosis of liver cancer patients. Collectively, these results provide evidence highlighting a transcription-dependent mechanism of ARID3A in stemness regulation in liver cancer. The ARID3A/CEP131-KDM3A regulatory circuit could serve as a prognostic indicator and potential therapeutic target for liver cancer.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Cycle Proteins / metabolism*
Cytoskeletal Proteins / metabolism*
DNA-Binding Proteins* / genetics
DNA-Binding Proteins* / metabolism
Embryonic Stem Cells / metabolism
Humans
Jumonji Domain-Containing Histone Demethylases / metabolism
Liver Neoplasms* / genetics
Liver Neoplasms* / metabolism
Promoter Regions, Genetic / genetics
Transcription Factors / metabolism*

Substances

ARID3A protein, human
CEP131 protein, human
Cell Cycle Proteins
Cytoskeletal Proteins
DNA-Binding Proteins
Transcription Factors
Jumonji Domain-Containing Histone Demethylases
KDM3A protein, human