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.
Highlights
Recurrence and metastasis remain the major obstacles to successful treatment of hepatocellular carcinoma (HCC)
We further reveal that C2H2 domain is required for ARID2–DNMT1 interaction and find loss-of-function ARID2 mutants with disrupted C2H2 domain are positively associated with HCC metastasis and poor survival of HCC patients
We found that DNA methylation approximate to the binding site of ARID2 and DNMT1 in Snail promoter was up-regulated in ARID2-overexpressing HCC cells and down-regulated in ARID2-knockdown HCC cells, which was coincident with DNMT1 binding (Fig. 4 K and L)
Summary
Recurrence and metastasis remain the major obstacles to successful treatment of hepatocellular carcinoma (HCC). 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. 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. 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. ARID2 inhibited migration and invasion of HCC cells in vitro and decreased the intrahepatic metastases and distant seeding of HCC cells in vivo. We discovered that the C2H2 mutants of ARID2 could not interact with DNMT1, losing the metastasis suppressor function.
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