Chromatin Remodeling Factor ARID2 Suppresses Hepatocellular Carcinoma Metastasis Via DNMT1-Snail Axis

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2020 Feb 20

PMID 32071245

Citations 59

Authors

Hao Jiang

Hui-Jun Cao

Ning Ma

Wen-Dai Bao

Jing-Jing Wang

Tian-Wei Chen

Er-Bin Zhang

Yan-Mei Yuan

Qian-Zhi Ni

Feng-Kun Zhang

Xu-Fen Ding

Qian-Wen Zheng

Yi-Kang Wang

Min Zhu

Xiang Wang

Jing Feng

Xue-Li Zhang

Shu-Qun Cheng

Dan-Jun Ma

Lin Qiu

Jing-Jing Li

Dong Xie

Affiliations

Soon will be listed here.

Abstract

Recurrence and metastasis remain the major obstacles to successful treatment of hepatocellular carcinoma (HCC). Chromatin remodeling factor ARID2 is commonly mutated in HCC, indicating its important role in cancer development. However, its role in HCC metastasis is largely elusive. In this study, we find that ARID2 expression is significantly decreased in metastatic HCC tissues, showing negative correlation with pathological grade, organ metastasis and positive association with survival of HCC patients. ARID2 inhibits migration and invasion of HCC cells in vitro and metastasis in vivo. Moreover, ARID2 knockout promotes pulmonary metastasis in different HCC mouse models. Mechanistic study reveals that ARID2 represses epithelial-mesenchymal transition (EMT) of HCC cells by recruiting DNMT1 to Snail promoter, which increases promoter methylation and inhibits Snail transcription. In addition, we discover that ARID2 mutants with disrupted C2H2 domain lose the metastasis suppressor function, exhibiting a positive association with HCC metastasis and poor prognosis. In conclusion, our study reveals the metastasis suppressor role as well as the underlying mechanism of ARID2 in HCC and provides a potential therapeutic target for ARID2-deficient HCC.

Citing Articles

Comprehensive systems biology analysis of microRNA-101-3p regulatory network identifies crucial genes and pathways in hepatocellular carcinoma.

Rahimi-Farsi N, Ghorbani A, Mottaghi-Dastjerdi N, Shahbazi T, Bostanian F, Mohseni P J Genet Eng Biotechnol. 2025; 23(1):100471.

PMID: 40074445 PMC: 11883376. DOI: 10.1016/j.jgeb.2025.100471.

FVTF inhibits hepatocellular carcinoma stem properties via targeting DNMT1/miR-34a-5p/FoxM1 axis.

Cao X, Peng J, Qiu Y, Zhu W, Cao J, Zou H Chin Med. 2025; 20(1):32.

PMID: 40050970 PMC: 11884036. DOI: 10.1186/s13020-025-01084-3.

Rescuing DNMT1 fails to fully reverse the molecular and functional repercussions of its loss in mouse embryonic stem cells.

Elder E, Lemieux A, Legault L, Caron M, Bertrand-Lehouillier V, Dupas T Nucleic Acids Res. 2025; 53(4).

PMID: 39997223 PMC: 11851107. DOI: 10.1093/nar/gkaf130.

Enhancing antitumor activity of herceptin in HER2-positive breast cancer cells: a novel DNMT-1 inhibitor approach.

Ren L, Song Y, Song Z, Yang H, Zhang Q, Ji M Discov Oncol. 2024; 15(1):640.

PMID: 39527385 PMC: 11555163. DOI: 10.1007/s12672-024-01508-w.

Opening and changing: mammalian SWI/SNF complexes in organ development and carcinogenesis.

Abu Sailik F, Emerald B, Ansari S Open Biol. 2024; 14(10):240039.

PMID: 39471843 PMC: 11521604. DOI: 10.1098/rsob.240039.

References

Szyf M, Detich N . Regulation of the DNA methylation machinery and its role in cellular transformation. Prog Nucleic Acid Res Mol Biol. 2001; 69:47-79. DOI: 10.1016/s0079-6603(01)69044-5. View

Wang T, Hu H, Feng Y, Shi J, Li N, Guo W . Characterisation of a novel cell line (CSQT-2) with high metastatic activity derived from portal vein tumour thrombus of hepatocellular carcinoma. Br J Cancer. 2010; 102(11):1618-26. PMC: 2883151. DOI: 10.1038/sj.bjc.6605689. View

Zhao H, Wang J, Han Y, Huang Z, Ying J, Bi X . ARID2: a new tumor suppressor gene in hepatocellular carcinoma. Oncotarget. 2011; 2(11):886-91. PMC: 3259997. DOI: 10.18632/oncotarget.355. View

Guichard C, Amaddeo G, Imbeaud S, Ladeiro Y, Pelletier L, Maad I . Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma. Nat Genet. 2012; 44(6):694-8. PMC: 3819251. DOI: 10.1038/ng.2256. View

Wilson B, Roberts C . SWI/SNF nucleosome remodellers and cancer. Nat Rev Cancer. 2011; 11(7):481-92. DOI: 10.1038/nrc3068. View

Lee E, Wang J, Yumoto K, Jung Y, Cackowski F, Decker A . DNMT1 Regulates Epithelial-Mesenchymal Transition and Cancer Stem Cells, Which Promotes Prostate Cancer Metastasis. Neoplasia. 2016; 18(9):553-66. PMC: 5031902. DOI: 10.1016/j.neo.2016.07.007. View

Fraga M, Herranz M, Espada J, Ballestar E, Paz M, Ropero S . A mouse skin multistage carcinogenesis model reflects the aberrant DNA methylation patterns of human tumors. Cancer Res. 2004; 64(16):5527-34. DOI: 10.1158/0008-5472.CAN-03-4061. View

Hodis E, Watson I, Kryukov G, Arold S, Imielinski M, Theurillat J . A landscape of driver mutations in melanoma. Cell. 2012; 150(2):251-63. PMC: 3600117. DOI: 10.1016/j.cell.2012.06.024. View

Raab J, Resnick S, Magnuson T . Genome-Wide Transcriptional Regulation Mediated by Biochemically Distinct SWI/SNF Complexes. PLoS Genet. 2015; 11(12):e1005748. PMC: 4699898. DOI: 10.1371/journal.pgen.1005748. View

10.

Bray F, Ferlay J, Soerjomataram I, Siegel R, Torre L, Jemal A . Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018; 68(6):394-424. DOI: 10.3322/caac.21492. View

11.

Oba A, Shimada S, Akiyama Y, Nishikawaji T, Mogushi K, Ito H . ARID2 modulates DNA damage response in human hepatocellular carcinoma cells. J Hepatol. 2017; 66(5):942-951. DOI: 10.1016/j.jhep.2016.12.026. View

12.

Wisnik E, Ploszaj T, Robaszkiewicz A . Downregulation of PARP1 transcription by promoter-associated E2F4-RBL2-HDAC1-BRM complex contributes to repression of pluripotency stem cell factors in human monocytes. Sci Rep. 2017; 7(1):9483. PMC: 5572705. DOI: 10.1038/s41598-017-10307-z. View

13.

Pan D, Kobayashi A, Jiang P, Ferrari de Andrade L, Tay R, Luoma A . A major chromatin regulator determines resistance of tumor cells to T cell-mediated killing. Science. 2018; 359(6377):770-775. PMC: 5953516. DOI: 10.1126/science.aao1710. View

14.

Sharif J, Muto M, Takebayashi S, Suetake I, Iwamatsu A, Endo T . The SRA protein Np95 mediates epigenetic inheritance by recruiting Dnmt1 to methylated DNA. Nature. 2007; 450(7171):908-12. DOI: 10.1038/nature06397. View

15.

Peinado H, Olmeda D, Cano A . Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype?. Nat Rev Cancer. 2007; 7(6):415-28. DOI: 10.1038/nrc2131. View

16.

Bigey P, Ramchandani S, Theberge J, Araujo F, Szyf M . Transcriptional regulation of the human DNA Methyltransferase (dnmt1) gene. Gene. 2000; 242(1-2):407-18. DOI: 10.1016/s0378-1119(99)00501-6. View

17.

Li M, Zhao H, Zhang X, Wood L, Anders R, Choti M . Inactivating mutations of the chromatin remodeling gene ARID2 in hepatocellular carcinoma. Nat Genet. 2011; 43(9):828-9. PMC: 3163746. DOI: 10.1038/ng.903. View

18.

Cajuso T, Hanninen U, Kondelin J, Gylfe A, Tanskanen T, Katainen R . Exome sequencing reveals frequent inactivating mutations in ARID1A, ARID1B, ARID2 and ARID4A in microsatellite unstable colorectal cancer. Int J Cancer. 2014; 135(3):611-23. DOI: 10.1002/ijc.28705. View

19.

Chen Z, Behringer R . twist is required in head mesenchyme for cranial neural tube morphogenesis. Genes Dev. 1995; 9(6):686-99. DOI: 10.1101/gad.9.6.686. View

20.

Ateeq B, Unterberger A, Szyf M, Rabbani S . Pharmacological inhibition of DNA methylation induces proinvasive and prometastatic genes in vitro and in vivo. Neoplasia. 2008; 10(3):266-78. PMC: 2259455. DOI: 10.1593/neo.07947. View