ARID1A deficiency promotes malignant proliferation of hepatocellular carcinoma by activating HDAC7/ENO1 signaling pathway

作者：Shanshan Zhang, Gang Wu, Lan Shi, Pengsheng Ding, Gan Liu, Wenjiao Chang, Yuanyuan Dai, Xinghua Han, Xiaoling Ma · 发表于：Hepatology Communications · 年份：2025 · DOI：10.1097/hc9.0000000000000738 · 被引用次数：8 · 研究领域：Chromatin Remodeling and Cancer、Histone Deacetylase Inhibitors Research、Genomics and Chromatin Dynamics

BACKGROUND: Epigenetic dysregulation constitutes one of the mechanisms in the pathogenesis of HCC, thereby underscoring its critical scientific importance for early diagnosis and therapeutic interventions. The chromatin remodeling factor AT-rich interaction domain 1A (ARID1A) serves as an essential epigenetic regulator and is frequently subject to inactivating mutations across various cancer types. Nevertheless, the precise molecular pathways by which ARID1A deficiency facilitates the progression of HCC remain inadequately elucidated. METHODS: RNA sequencing (RNA-seq) was employed to identify genes that were significantly upregulated following the knockdown of ARID1A. Immunohistochemistry was used to assess the expression levels of ARID1A and histone deacetylase 7 (HDAC7) in HCC samples. Chromatin immunoprecipitation and luciferase reporter assays were conducted to validate PU.1 as a positive transcriptional regulator of HDAC7. Protein immunoprecipitation coupled with mass spectrometry was used to identify potential substrates of HDAC7. A xenograft assay was performed to evaluate the therapeutic potential of HDAC7 inhibitors in ARID1A-deficient HCC. RESULTS: Our investigation demonstrated that the loss of ARID1A in HCC cells led to an upregulation of HDAC7 expression. Mechanistic analyses revealed that ARID1A deficiency facilitated PU.1-mediated transcriptional regulation of HDAC7. Additionally, the overexpression of HDAC7 resulted in a reduced acetylation level of Enolase 1 ...