Abstract
JARID1B is a member of the family of JmjC domain-containing proteins that removes methyl residues from methylated lysine 4 on histone H3 lysine 4 (H3K4). JARID1B has been proposed as an oncogene in many types of tumors; however, its role and underlying mechanisms in hepatocellular carcinoma (HCC) remain unknown. Here we show that JARID1B is elevated in HCC and its expression level is positively correlated with metastasis. In addition Kaplan-Meier survival analysis showed that high expression of JARID1B was associated with decreased overall survival of HCC patients. Overexpression of JARID1B in HCC cells increased proliferation, epithelial-mesenchymal transition, migration and invasion in vitro, and enhanced tumorigenic and metastatic capacities in vivo. In contrast, silencing JARID1B in aggressive and invasive HCC cells inhibited these processes. Mechanistically, we found JARID1B exerts its function through modulation of H3K4me3 at the PTEN gene promoter, which was associated with inactive PTEN transcription. PTEN overexpression blocked JARID1B-driven proliferation, EMT, and metastasis. Our results, for the first time, portray a pivotal role of JARID1B in stimulating metastatic behaviors of HCC cells. Targeting JARID1B may thus be a useful strategy to impede HCC cell invasion and metastasis.
Highlights
The incidence of hepatocellular carcinoma (HCC) has dramatically increased in Western countries and has become more prevalent in Asian countries [1, 2]
To investigate whether Jumonji AT-rich interactive domain 1B (JARID1B) might be involved in HCC, the mRNA expression level of JARID1B in HCC tissues and its matched normal adjacent tissues was determined by qRT-PCR in 38 samples
We analyzed JARID1B expression in HCCs without or with distant metastasis; we found that JARID1B mRNA overexpression was significantly correlated with distant metastasis in HCC tissues (Figure. 1C)
Summary
The incidence of hepatocellular carcinoma (HCC) has dramatically increased in Western countries and has become more prevalent in Asian countries [1, 2]. Significant improvement in diagnosis and treatment of HCC has been achieved, the outcome of patients remains dismal with a median survival of merely a few months [3]. This poor prognosis is due to high recurrent and metastatic rates even after the use of current treatment modalities [3]. Biomarkers that are currently used clinically to predict the prognosis of HCC patients after curative surgical resection remain unsatisfactory in terms of both accuracy and reproducibility It www.impactjournals.com/oncotarget remains clinically important to identify novel prognostic biomarkers to improve the diagnosis and treatment of HCC patients. JARID1B may act as an oncogene, but whether JARID1B plays a role in HCC formation and metastasis remains unknown
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