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Published on: September 12, 2019
Arid1a regulates response to anti-angiogenic therapy in advanced hepatocellular carcinoma
Chaobo Hu1, Weiping Li1, Feng Tian2
1State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences; University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
Background & Aims:
AT-rich interaction domain 1a (Arid1a), a component of the chromatin remodeling complex, has emerged as a tumor suppressor gene. It is frequently mutated in hepatocellular carcinoma (HCC). However, it remains unknown how Arid1a suppresses HCC development and whether Arid1a deficiency could be exploited for therapy, we aimed to explore these questions.
Methods:
The expression of Arid1a in human and mouse HCCs was determined by immunohistochemical (IHC) staining. Gene expression was determined by quantitative PCR, ELISA or western blotting. Arid1a knockdown HCC cell lines were established by lentiviral-based shRNA. Tumor angiogenesis was quantified based on vessel density. The regulation of angiopoietin (Ang2) expression by Arid1a was identified by chromatin immunoprecipitation (ChIP) assay. The tumor promoting function of Arid1a loss was studied with a xenograft model in nude mice and diethylnitrosamine (DEN)-induced HCC in Arid1a conditional knockout mice. The therapeutic values of Ang2 antibody and sorafenib treatment were evaluated both in vitro and in vivo.
Results:
We demonstrate that Arid1a deficiency, occurring in advanced human HCCs, is associated with increased vessel density. Mechanistically, loss of Arid1a causes aberrant histone H3K27ac deposition at the angiopoietin-2 (Ang2) enhancer and promoter, which eventually leads to ectopic expression of Ang2 and promotes HCC development. Ang2 blockade in Arid1a-deficient HCCs significantly reduces vessel density and tumor progression. Importantly, sorafenib treatment, which suppresses H3K27 acetylation and Ang2 expression, profoundly halts the progression of Arid1a-deficient HCCs.
Conclusions:
Arid1a-deficiency activates Ang2-dependent angiogenesis and promotes HCC progression. Loss of Arid1a in HCCs confers sensitivity to Ang2 blockade and sorafenib treatment.
Lay Summary:
AT-rich interaction domain 1a (Arid1a), is a tumor suppressor gene. Arid1a-deficiency promotes Ang2-dependent angiogenesis leading to hepatocellular carcinoma progression. Arid1a-deficiency also sensitizes tumors to Ang2 blockade by sorafenib treatment.
Insights
AT-rich interaction domain 1a (Arid1a) loss promotes hepatocellular carcinoma (HCC) by activating Ang2-dependent angiogenesis. Arid1a-deficient HCCs show increased sensitivity to Ang2 blockade and sorafenib, offering potential therapeutic strategies.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- AT-rich interaction domain 1a (Arid1a) is a tumor suppressor frequently mutated in hepatocellular carcinoma (HCC).
- The precise mechanisms by which Arid1a loss promotes HCC and its therapeutic implications remain largely unexplored.
Purpose of the Study:
- To elucidate how Arid1a deficiency drives HCC development.
- To investigate the potential of targeting Arid1a-deficient HCCs for therapy.
Main Methods:
- Assessed Arid1a expression in human and mouse HCCs via immunohistochemistry.
- Utilized quantitative PCR, ELISA, and western blotting for gene expression analysis.
- Established Arid1a-knockdown HCC cell lines and employed xenograft and diethylnitrosamine-induced HCC models in mice.
- Quantified tumor angiogenesis and investigated Arid1a's regulation of angiopoietin-2 (Ang2) using chromatin immunoprecipitation assays.
- Evaluated therapeutic efficacy of Ang2 antibody and sorafenib treatment in vitro and in vivo.
Main Results:
- Arid1a deficiency in advanced HCC correlates with increased tumor vessel density.
- Loss of Arid1a leads to aberrant histone H3K27 acetylation at the Ang2 enhancer/promoter, causing ectopic Ang2 expression and promoting HCC.
- Ang2 blockade significantly reduces vessel density and tumor progression in Arid1a-deficient HCCs.
- Sorafenib treatment inhibits H3K27 acetylation and Ang2 expression, halting HCC progression.
Conclusions:
- Arid1a deficiency promotes HCC progression through Ang2-dependent angiogenesis.
- Loss of Arid1a renders HCCs sensitive to Ang2 blockade and sorafenib therapy.
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