Depletion of histone demethylase KDM5B inhibits cell proliferation of hepatocellular carcinoma by regulation of cell cycle checkpoint proteins p15 and p27

Abstract

BackgroundKDM5B is a jmjc domain-containing histone demethylase which remove tri-, di-, and monomethyl groups from histone H3 lysine 4 (H3K4). KDM5B has been determined as an oncogene in many malignancies. However, its expression and role in hepatocellular carcinoma (HCC) remain unknown.MethodsWe detected the expression of KDM5B in HCC tissues and cell lines. Cell proliferation was performed to reveal the role of KDM5B depletion on HCC cells both in vivo and in vitro. Flow cytometry was used to analyze the cell cycle and chip analysis was conducted to determine the direct target of KDM5B.ResultsKDM5B is frequently up-regulated in HCC specimens compared with adjacent normal tissues and its expression level was significantly correlated with tumor size, TNM stage, and Edmondson grade. Moreover, Kaplan-Meier survival analysis showed that patients with high levels of KDM5B expression had a relatively poor prognosis. Knockdown of KDM5B notably inhibits HCC cell proliferation both in vivo and in vitro via arresting the cell cycle at G1/S phase partly through up-regulation of p15 and p27. Further molecular mechanism study indicates that silencing of KDM5B promotes p15 and p27 expression by increasing histone H3K4 trimethylation in their promoters.ConclusionsKDM5B could be a potentially therapeutic target, which provides a rationale for the development of histone demethylase inhibitors as a strategy against HCC.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-016-0311-5) contains supplementary material, which is available to authorized users.

Lysine-Specific Histone Demethylases Contribute to Cellular Differentiation and Carcinogenesis

“…On the other hand, knockdown of KDM5B in hepatocellular carcinoma cells (HCCs) inhibits cell proliferation via cell cycle arrest at the G1/S phase. 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].…”

JARID1 Histone Demethylases: Emerging Targets in Cancer

“…This effect is maintained in hepatocellular cancer [6] and is also described in lung cancers via JARID1A [46]. JARID1A and JARID1B-mediated repression of other cdk inhibitors is also reported, including effects on p15, p16, and p21 [6, 12, 48, 49]. It remains unclear what contextual determinants dictate whether JARID1 proteins drive G 1 -S progression or promote arrest and senescence.…”

“…JARID1B amplification and overexpression are strongly associated with poor prognosis in hormone receptor-positive tumors and drive a luminal-type gene expression profile [4]. It is also upregulated in numerous other cancers including prostate [5], hepatocellular [6], and ovarian [7]. Despite low JARID1B levels in melanomas relative to benign nevi [8], these cancers contain a fraction of cells where high JARID1B expression confers stem cell-like molecular and functional traits [9], drives oxidative metabolism, and increases drug resistance [10].…”

“…Repression of the p27 promoter is another JARID1B-mediated mechanism of G 1 -S progression that was first observed in normal embryos [47]. This effect is maintained in hepatocellular cancer [6] and is also described in lung cancers via JARID1A [46]. JARID1A and JARID1B-mediated repression of other cdk inhibitors is also reported, including effects on p15, p16, and p21 [6, 12, 48, 49].…”

Long non‐coding RNA FOXP4‐AS1 is an unfavourable prognostic factor and regulates proliferation and apoptosis in colorectal cancer

“…Many studies have demonstrated that lncRNAs contribute to cancer cell phenotypes by silencing tumour suppressors or activating oncogenes . In addition, many cell cycle‐related genes (including p15, p21, p27 and KLF2) act as tumour suppressors in various cancers by inhibiting the activity of kinases involved in the G1/S transition . Our previous studies have demonstrated that lncRNA BANCR (BRAF activated non‐coding RNA) promotes CRC cell proliferation partly by down‐regulating p21 expression …”