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Lysine-specific demethylase 5C promotes hepatocellular carcinoma cell invasion through inhibition BMP7 expression
- Xuening Ji†1,
- Shi Jin†2,
- Xiaotong Qu3,
- Kejun Li2,
- Hongjiang Wang4,
- Hui He2,
- Fuchao Guo5Email author and
- Lei Dong2Email author
© Ji et al. 2015
Received: 3 July 2015
Accepted: 16 October 2015
Published: 26 October 2015
Hepatocellular carcinoma (HCC) is the most common type of tumor and is associated with high morbidity and mortality rates. Patients with HCC routinely undergo surgery followed by adjuvant radiation therapy and chemotherapy. Despite such aggressive treatment approaches, median survival times remain under 1 year in most cases. KDM5C 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). KDM5C has been proposed as an oncogene in many types of tumors; however, its role and underlying mechanisms in HCC remain unclear.
Expression level of KDM5C was examined by RT-PCR, and IHC. Forced expression of KDM5C was mediated by retroviruses, and KDM5C was downregulated by shRNAs expressing lentiviruses. Migration and invasion of HCC cells was measured by wound healing, Transwell and Matrigel assays respectively.
In this study, we report that KDM5C is abundantly expressed in invasive human HCC cells. Cellular depletion of KDM5C by shRNA inhibited HCC cell migration, invasion and epithelial-mesenchymal transition in vitro, and markedly decreased the metastasis capacity of invasive HCC cells in the liver and lung. Furthermore, ectopic expression of KDM5C in HCC cells promoted cell migration, invasion and epithelial-mesenchymal transition via the inactivation of BMP7. Knockdown of BMP7 significantly promotes shKDM5C-induced cell migration inhibition.
Taken together, these data suggest that KDM5C-mediated BMP7 inactivation is essential for HCC cell invasion.
Hepatocellular carcinoma (HCC) is a highly aggressive tumor characterized by its lack of response to conventional chemo-, radio-, and immunotherapies . HCC cells extensively invade normal tissues, which contribute to the continued poor prognosis for these tumors by preventing complete surgical resection [2, 3]. Invading tumor cells are resistant to conventional therapies and invasiveness is enhanced by antiangiogenic approaches [4, 5]. Thus, an effective strategy to prevent invasion of HCC cells into surrounding normal tissues is needed.
Lysine (K)-specific demethylase 5C (KDM5C) is a member of the family of JmjC domain-containing proteins that specifically removes methyl residues from tri-, di-, and monomethylated lysine 4 on histone H3 lysine 4 (H3K4) that are associated with active genes . KDM5C is a transcriptional repressor that harbors intrinsic histone demethylase activity . Trimethylation at H3K4 is an important histone mark associated with actively transcribed genes, and KDM5C specifically demethylates H3K4me3 to a transcriptionally inactive state . KDM5C is up-regulated in multiple tumor cell lines [9–11]. Furthermore, KDM5C promotes proliferation of cancer cells, and knockdown of KDM5C causes a significant delay in the G1/S transition [12, 13]. KDM5C appears to promote tumorigenesis through the specific repression of antiproliferative genes [14, 15]. Thus, KDM5C may act as an oncogene, but whether KDM5C plays a role in HCC metastasis remains unknown.
Bone morphogenetic proteins (BMPs) signal via specific serine/threonine kinase receptors on the cell surface known as bone morphogenetic protein receptors (BMPRs) . Both type-I and -II BMPRs are required for signal transduction. The type-I receptor BMPRIA preferentially binds ligands of the Dpp class, such as BMP2 and BMP4, whereas the type-II receptor BMPRIB binds ligands of the 60A class, such as BMP7 [16–18]. After ligand binding, the type-I/type-II receptor complex phosphorylates Smad1, 5 and 8 proteins that translocate to the nucleus to regulate target gene expression . Previous studies have shown that BMP-7 exert anti-invasive actions by inhibiting TGF-beta-induced expression of integrin beta [20, 21].
In the current study, we show that KDM5C overexpression predicts poor prognosis in HCC patients undergoing curative resection. Additionally, we present the evidence that KDM5C expression promotes HCC cells invasion, metastasis and EMT. These functional effects of KDM5C were exerted through control of BMP7 transcriptional expression via H3K4me3. The down-regulation of BMP7 triggered by KDM5C therefore enforces HCC cells oncogenesis and metastasis. Our findings provide a novel mechanistic role of KDM5C in HCC metastasis, suggesting that KDM5C may serve as a potential therapeutic target for advanced HCCs.
Chemicals and antibodies
Lipofectamine 2000 transfection and TRIZOL LS Reagents were purchased from Invitrogen (Grand Island, NY, USA). Antibodies against KDM5C, Histone H3, H3K4me1 (monomethylated K4), H3K4me2 (dimethylated K4), H3K4me3 (trimethylated K4), H3K27me3 (trimethylated K27) were purchased from Abcam (Cambridge, MA, USA). E-cadherin, N-cadherin, vimentin, BMP7, and β-actin antibodies were from Cell Signaling technology (Danvers, MA, USA). Anti-α-catenin antibody was from BD (Franklin Lakes, NJ, USA).
Patients and specimens
KDM5C staining and clinicopathologic characteristics of 221 hepatocellular carcinoma patients
61 (73 %)
22 (27 %)
99 (72 %)
39 (28 %)
133 (73 %)
49 (27 %)
31 (79 %)
8 (21 %)
46 (80 %)
11 (20 %)
115 (60 %)
49 (40 %)
139 (66 %)
72 (34 %)
8 (80 %)
2 (20 %)
73 (75 %)
25 (25 %)
91 (74 %)
32 (26 %)
72 (67 %)
36 (33 %)
81 (72 %)
32 (28 %)
29 (69 %)
13 (31 %)
122 (68 %)
57 (32 %)
Tumor diameter (cm)
133 (68 %)
62 (32 %)
12 (46 %)
14 (54 %)
74 (80 %)
19 (20 %)
53 (41 %)
75 (59 %)
78 (74 %)
27 (26 %)
77 (66 %)
39 (34 %)
I + II
115 (73 %)
42 (27 %)
III + IV
26 (41 %)
38 (59 %)
121 (64 %)
68 (36 %)
II + III
23 (72 %)
9 (28 %)
Histological and immunohistochemical analysis
The normal human liver tissues, human tumor tissues, and lungs dissected from mice were fixed in 4 % paraformaldehyde in phosphate-buffered saline (PBS) overnight and subsequently embedded in paraffin wax. Sections cut at a thickness of 4 μm were stained with hematoxylin and eosin for histological analysis. Immunohistochemical analysis was performed for different markers in these arrays as described previously. The proportion of stained cells (lower, <30 % staining; higher, ≥30 % staining) was semiquantitatively determined following published protocols [22, 23].
HCC cells (ATCC, Manassas, VA, USA) were cultured under the following conditions: Huh7, and MHCC97L cell lines were cultured using 10 % fetal bovine serum (Cat#10099-141, Invitrogen, Carlsbad, CA) in either RPMI-1640 (Cat#C11875, Invitrogen). L02 cell lines were cultured using 10 % fetal bovine serum (Invitrogen) in Dulbecco’s modified Eagle medium (Cat#C11965, Invitrogen). Cell culture was according to manufacturer’s protocol. All the cell lines were grown at 37 °C in a 5 % CO2/95 % air atmosphere and were revived every 3 to 4 months.
Establishment of KDM5C and BMP7 stable expression and KDM5C and BMP7 knockdown cell lines
Retroviral construct containing human pBabe-KDM5C cDNA, pcDNA3.1-BMP7 cDNA and pSuper.retro.puro with shRNA against human KDM5C and siBMP7 were prepared as described previously [22, 24]. The generation of retrovirus supernatants and transfection of hepatocellular carcinoma cells were conducted as described previously [22, 25]. The expression of KDM5C and BMP7 was confirmed by qRT-PCR and Western blotting analysis.
Wound healing assay
Cells were seeded in 6 cm culture plates, and the cell monolayers were wounded by scratching with sterile plastic 200 μl micropipette tips and photographed using phase-contrast microscopy. The migration distance of each cell was measured after the photographs were converted to Photoshop files.
Cell invasion and motility assay
Invasion of cells was measured in Matrigel (BD, Franklin Lakes, NJ, USA) -coated Transwell inserts (6.5 mm, Costar, Manassas, VA, USA) containing polycarbonate filters with 8-μm pores as detailed previously. The inserts were coated with 50 μl of 1 mg/ml Matrigel matrix according to the manufacturer’s recommendations. 2 × 105 cells in 200 μl of serum-free medium were plated in the upper chamber, whereas 600 μl of medium with 10 % fatal bovine serum were added to lower well. After 24 h incubation, cells that migrated to the lower surface of the membrane were fixed and stained. For each membrane, five random fields were counted at × 10 magnification. Motility assays were similar to Matrigel invasion assay except that the Transwell insert was not coated with Matrigel.
Cells were lysed in lysis buffer and total protein contents were determined by the Bradford method. 30 μg of lysis were separated by reducing SDS-PAGE and probed with specific antibodies. Blots were washed and probed with respective secondary peroxidase-conjugated antibodies, and the bands visualized by chemoluminescence (Amersham Biosciences).
Total RNA was extracted using Trizol reagent and cDNA was synthesized using SuperScript II Reverse Transcriptase (Invitrogen). qRT-PCR and data collection were performed with an ABI PRISM 7900HT sequence detection system. The primers used for the amplification of the indicated genes are available in Additional file 1: Table S1.
Gene expression profiling
Total RNA quality and quantity were determined using Agilent 2100 Bioanalyzer and NanoDrop ND-1000. Affymetrix HU U133 plus 2.0 arrays were used according to manufacturer’s protocol. The data were initially normalized by robust multiarray average (RMA) normalization algorithms in expression console software (Affymetrix). Significantly altered genes between KDM5C overexpression and its control cells were considered by scatter plots and the genes up- and down-regulated ≥5-fold. Clustering analysis was done using gene list by Gene Cluster v3.0 software, and heat maps were visualized using Java TreeView v1.1.4r3 software. Gene set enrichment analysis was carried out using ConceptGen (http://conceptgen.ncibi.org/core/conceptGen/index.jsp). Gene sets were either obtained from the ConceptGen or from published gene signatures.
Chromatin immunoprecipitation (ChIP)-qPCR
Chromatin Immunoprecipitation kit (Cat. 17–371) was purchased from Millipore and ChIP experiments were carried out essentially as described . Immnuoprecipitated DNA was analyzed on the ABI PRISM 7900HT sequence detection system. The primers used for detection of promoters after ChIP are available upon request.
In vivo tumor metastasis assays
Nude mice were purchased from the Shanghai Slac Laboratory Animal Co. Ltd and maintained in microisolator cages. All animals were used in accordance with institutional guidelines and the current experiments were approved by the the Dalian Medical University Experimental Animal Care Commission. For metastasis assays, cells were resuspended in PBS at a concentration of 1×107 cells ml−1. Cell suspension (0.1 ml) was injected into tail veins of nude mice. All of the mice were killed by CO2 60 days after inoculation.
Results were analyzed with SPSS13.0 statistical software. Correlation between KDM5C expression and clinicopathologic parameters was evaluated using the Chi-square (χ2) test, and quantitative variables were analyzed by the independent t test. The survival probability was estimated by Kaplan-Meier method, and the comparison of survival curves between groups was done with the log-rank test. The statistical significance of the differences between mean values was determined by P < 0.05.
KDM5C is highly expressed and correlated with distant metastasis in HCC
Transfection efficiency of KDM5C in HCC cell lines
KDM5C promotes migratory and invasive capacities of HCC cells in vitro
KDM5C promotes HCC cells metastasis in vivo
KDM5C regulates the transition between epithelial and mesenchymal phenotypes in HCC cells
KDM5C regulates BMP7 expression through H3K4 trimethylation
Hepatocellular carcinoma (HCC) is the fifth most common malignancy in the world and the second leading cause of cancer death in Asia . The high mortality rate of HCC is caused by frequent tumor metastasis, postsurgical recurrence, and late detection at advanced stages . HCC is associated with multiple risk factors and is now recognized as a both genetic and epigenetic disease [29, 30]. While the sequential accumulation of various genetic changes in hepatocarcinogenesis has been extensively studied, the contribution of epigenetic alterations to HCC development and progression has remained relatively poorly understood. Histone methylation is a dynamic epigenetic process that participates in a diverse array of cellular processes and has been found to associate with cancer, including HCC . Recently, several histone demethylases have been identified that catalyze the removal of methylation from histone H3 lysine residues [13, 31]. Previous studies had found that KDM5C, also named JARID1C, as a histone demethylase that can catalyze the removal of all three methyl groups from the H3K4 lysine residue . However, its role and underlying mechanisms in HCCs still unknown.
To our knowledge, this is the first research to show that KDM5C plays an important role in HCC. We found that as compared with normal tissues, HCC specimens showed overexpression of KDM5C and its overexpression was significantly correlated with distant metastasis in HCC tissues. High expression of KDM5C was associated with decreased overall survival of HCC patients. KDM5C overexpression in HCC cells induced EMT, migration, invasion in vitro and enhanced metastatic capacities in vivo. In contrast, silencing KDM5C reversed these events in invasive HCC cells. We also showed that a mechanistic link between KDM5C and BMP7 through KDM5C-mediated regulation of H3K4m3, which subsequently leads to transcriptional downregulation of BMP7 expression. These results lead us to propose a model for KDM5C regulation of EMT and metastasis through transcriptional regulation of BMP7 in HCCs.
Histone lysine demethylases (KDMs) are epigenetic enzymes that can remove both repressive and activating histone marks . KDM5 family members are capable of removing the histone H3 lysine 4 dimethylation-activating marks, rendering them potential players in the down-regulation of tumor suppressors and suggesting that their activity could repress oncogenes . Histone demethylase KDM5C is required for proper DNA replication at early origins . KDM5C dictates the assembly of the pre-initiation complex, driving the binding to chromatin of the pre-initiation proteins, through the demethylation of the histone mark H3K4me3 . The putative role of KDM5C as an oncogene in cancer development is supported by the observations that KDM5C is highly expressed in prostate cancer and other malignant tumors relative to normal tissues . Consistent with this research, in the present study we showed that overexpression of KDM5C promoted HCC cells proliferation and enhanced tumor formation in vivo. Interestingly, our study points to a novel function of KDM5C in HCC metastasis through regulating EMT.
HCC cells with ectopic expression of KDM5C displayed an EMT phenotype, including the associated stimulatory effects on migration and invasion in vitro. Interestingly, our results indicate that KDM5C not only promotes EMT, but silencing of KDM5C also leads to MET. All of these characteristics induced by KDM5C in vitro culminated to increased numbers of distant metastases in vivo. These empirical findings provide a mechanistic framework to explain the clinical observations that HCC patients with high levels of KDM5C in tissue samples have more chance of distant metastasis, a significantly shorter overall and disease-free survival.
Bone morphogenetic proteins (BMPs) are secreted signaling molecules belonging to the transforming growth factor (TGF)-beta superfamily . Recent studies demonstrated that the expression patterns of BMP7 are altered in several tumors. BMP7 is essential during development, and more recently has also been implicated in cancer pathogenesis . The roles of several transcription factors as EMT regulators have been extensively reported . In our effort to elucidate the mechanism how KDM5C modulates EMT in HCC cells, we identified BMP7 as an effective mediator of KDM5C-induced these phenomena. BMP7 is one of the most frequently mutated tumor suppressors in human cancer including HCCs . BMP7 also suppresses migration, genetic deletion of the BMP7 tumor suppressor gene promotes cell motility, and BMP7 reconstitution or overexpression inhibits cell motility in some cell types [20, 35]. Mechanistically, BMP7 reduces cell motility through a variety of pathways, and decreased ERK and AKT are two important targets of BMP7 . The mechanistic connection between KDM5C and BMP7 was previously unknown. In this study, we showed that modulation of KDM5C expression altered the methylation status of H3K4 at the BMP7 gene promoter, which in turn transcriptionally controlled expression of BMP7. However, we did not detect any influence of KDM5C expression on the methylation status of H3K27. Thus, we conclude that KDM5C transcriptionally inactivates BMP7 expression through H3K4 demethylation and reduces H3K4me3 to the BMP7 gene promoter, and consequently resulting in increase in migration and invasion both in vitro and in vivo.
In conclusion, we found that KDM5C expression was generally higher in HCC lesions compared with non-tumor tissues. Our in vitro and in vivo data demonstrate that KDM5C has a vital function in promoting cell mobility, which is partially by the regulation of BMP7 expression. Thus, we propose that the candidate tumor oncogene KDM5C may be an effective novel therapeutic target in the management of HCC.
This research was supported in part by The Natural Science Foundation of Liaoning Province (No. 2014023022).
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