JARID1B promotes metastasis and epithelial-mesenchymal transition via PTEN/AKT signaling in hepatocellular carcinoma cells

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.

Lysine-Specific Histone Demethylases Contribute to Cellular Differentiation and Carcinogenesis

“…In agreement with in vivo data, melanoma cell lines exhibit low and heterogeneous levels of KDM5A expression [134]. KDM5B (JARID1B) has been described as a putative oncogene in several cancers, and its level of expression is correlated with tumor malignancy [135][136][137][138]. The KDM5B-mediated H3K4 demethylase activity plays an important role in the proliferative capacity of breast cancer cells through repression of tumor suppressor genes, including BRCA1 [135][136][137][138].…”

“…In this case, KDM5B induces the expression of key cell regulatory genes (e.g., p15 and p27) by removing the methylation mark of histone H3K4me3 from their promoters [139]. Consistent with these data, KDM5B overexpression in HCCs increases proliferation, EMT, migration, and invasion in vitro, and enhances tumorigenic and metastatic capacities in vivo [137].…”

“…KDM5B (JARID1B) has been described as a putative oncogene in several cancers, and its level of expression is correlated with tumor malignancy [135][136][137][138]. The KDM5B-mediated H3K4 demethylase activity plays an important role in the proliferative capacity of breast cancer cells through repression of tumor suppressor genes, including BRCA1 [135][136][137][138]. Similar to breast cancer, KDM5B is upregulated also in prostate cancer tissues as compared to benign prostate samples.…”

Hypoxia Promotes Resistance to EGFR Inhibition in NSCLC Cells via the Histone Demethylases, LSD1 and PLU-1

“…In addition, PLU-1 has been reported to promote drug resistance in melanomas (26) and to drive metastasis and EMT in hepatocellular cancer cells (27), while LSD1 has been shown to promote invasion and metastasis through facilitating EMT in many cancer cell types (28–30). These studies provided a further rationale for the investigation of whether PLU-1 and/or LSD1 play a role in hypoxia induced gefitinib resistance in HCC827 cells.…”

JARID1 Histone Demethylases: Emerging Targets in Cancer

“…JARID1B was recently implicated in activating Akt in hepatocellular carcinoma and hypopharyngeal squamous cell carcinoma via direct suppression of the promoters for the PTEN [50] and SHIP1 [51] phosphatases, respectively, thus providing a new basis for the epigenetic suppression of PTEN widely observed in cancer. Notably, ectopic Akt activation also increases JARID1B levels in oral cancer cells, suggesting that the PI3K pathway itself drives JARID1B upregulation [11] by presently unknown mechanisms.…”