Chromatin remodeling factor ARID2 suppresses hepatocellular carcinoma metastasis via DNMT1-Snail axis

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.

Exosome-derived miR-142-5p remodels lymphatic vessels and induces IDO to promote immune privilege in the tumour microenvironment

“…As a subunit of the polybromo-associated BAF (PBAF) complex, ARID2 potentially interacts with epigenetic regulators and modulates gene transcription [ 28 ]. A recent study reported that DNMT1 was recruited as an epigenetic modulator by ARID2 to enhance the methylation of Snail promoter [ 29 ]. This observation promoted us to investigate the involvement of the ARID2-DNMT1 complex in the regulation of IFN-γ transcription.…”

“…Chromatin remodelling molecules often regulate gene expression by cooperating with epigenetic modulators, such as the E2F4-RBL2-HDAC1-BRM complex involved in proline-rich acidic protein 1 (PRAP1) transcriptional repression [ 50 ]. A recent study confirmed the recruitment of DNMT1 as an epigenetic modulator by ARID2 to enhance the methylation of gene promoter [ 29 ] that led us to investigate whether the ARID2-DNMT1 complex was also involved in the regulation of IFN-γ transcription. We verified the co-occupancy of ARID2 and DNMT1 at the same region of the IFN-γ promoter.…”

Tackle Epithelial-Mesenchymal Transition With Epigenetic Drugs in Cancer

“…On the other hand, because DNMT inhibitors can reverse the hypermethylated state at the promoters of epithelial markers such as E-cadherin, they also induce the activation of pro-metastatic genes. For instance, a most recent work indicates that DNMT1 can be recruited by a subunit of the chromatin remodeling complex to the Snail promoter and suppress its transcription, therefore downregulation of DNMT1 could also induce expression of EMT-TFs (Jiang et al, 2020). Consequently, targeting the DNA methylation readers like MBDs may provide a suitable alternative for the next generation of epigenetic therapies, and several studies have shown promising effects in terms of developing anticancer therapeutic strategies against the MBDs (Mahmood and Rabbani, 2019).…”

ARID2 Chromatin Remodeler in Hepatocellular Carcinoma

“…Duan et al suggested a mechanism through which ARID2 controls cell proliferation by regulating the expression of cell cycle components. More recently, Jiang et al described ARID2 downregulation in metastatic HCC, in association with poor prognoses [ 74 ]. ARID2-Kd was associated with increased migration and invasion in HCC cell lines whereas ARID2 over-expression in HCC cell lines and their related metastatic derivative inhibited invasion and migration.…”