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Chromatin remodeling factor ARID2 suppresses hepatocellular carcinoma metastasis via DNMT1-Snail axis
Hao Jiang1,2,3, Hui-Jun Cao1, Ning Ma1
1CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 200031 Shanghai, China.
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.
Insights
Chromatin remodeling factor ARID2 suppresses hepatocellular carcinoma (HCC) metastasis by inhibiting epithelial-mesenchymal transition (EMT). Decreased ARID2 levels correlate with poor prognosis, suggesting ARID2 as a therapeutic target for HCC.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Hepatocellular carcinoma (HCC) metastasis is a primary challenge in treatment.
- Mutations in the chromatin remodeling factor ARID2 are common in HCC, but its role in metastasis is unclear.
Purpose of the Study:
- To investigate the role of ARID2 in HCC metastasis.
- To elucidate the underlying molecular mechanisms of ARID2's function in HCC.
Main Methods:
- Analysis of ARID2 expression in HCC tissues correlated with clinical parameters.
- In vitro cell migration and invasion assays.
- In vivo metastasis models in mice.
- Mechanistic studies involving DNMT1 recruitment and Snail promoter methylation.
Main Results:
- ARID2 expression is reduced in metastatic HCC and correlates with better patient survival.
- ARID2 inhibits HCC cell migration, invasion, and metastasis in vivo.
- ARID2 represses epithelial-mesenchymal transition (EMT) by recruiting DNMT1 to the Snail promoter, suppressing Snail transcription.
- ARID2 mutants lacking functional C2H2 domains lose metastasis suppressor activity.
Conclusions:
- ARID2 acts as a metastasis suppressor in HCC.
- ARID2 functions by repressing EMT through epigenetic regulation of Snail.
- ARID2 deficiency is linked to poor prognosis, identifying it as a potential therapeutic target for HCC.
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