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

Tang B, Qi G, Tang F, Yuan S, Wang Z, Liang X, Li B, Yu S, Liu J, Huang Q, Wei Y, Zhai R, Lei B, Yu H, Jiao X, He S - Oncotarget (2015)

Bottom Line: In addition Kaplan-Meier survival analysis showed that high expression of JARID1B was associated with decreased overall survival of HCC patients.Mechanistically, we found JARID1B exerts its function through modulation of H3K4me3 at the PTEN gene promoter, which was associated with inactive PTEN transcription.Our results, for the first time, portray a pivotal role of JARID1B in stimulating metastatic behaviors of HCC cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Hepatobiliary Surgery, Guilin Medical University, Affiliated Hospital, Guilin, Guangxi, People's Republic of China.

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.

No MeSH data available.


Related in: MedlinePlus

JARID1B regulates PTEN transcriptional expression through H3K4 trimethylationA and B, the abundance of H3 lysine methylation was assessed in HCC cells with JARID1B overexpression (A) or silencing (B) by Western blotting using whole-cell lysate; total H3 and β-actin were used as a loading control. C, schematic presentation of three regions relative to the PTEN transcriptional start site used as primers to test histone occupied abundance. D and E, qChIP was performed to assess H3K4me3 occupancy in HepG2-pBabe-JARID1B (D), SK-Hep1-pSuper-shJARID1B (E) or their control cells. IgG was used as negative control (D and E, left). “Percentage of input” indicates the ratio of DNA fragment of each promoter region bound by H3K4me3 to the total amount of input DNA fragment without H3K4me3 antibody pull-down. **, P < 0.01 is based on the Student t test. All results are from three independent experiments. Error bars, SD.
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Figure 8: JARID1B regulates PTEN transcriptional expression through H3K4 trimethylationA and B, the abundance of H3 lysine methylation was assessed in HCC cells with JARID1B overexpression (A) or silencing (B) by Western blotting using whole-cell lysate; total H3 and β-actin were used as a loading control. C, schematic presentation of three regions relative to the PTEN transcriptional start site used as primers to test histone occupied abundance. D and E, qChIP was performed to assess H3K4me3 occupancy in HepG2-pBabe-JARID1B (D), SK-Hep1-pSuper-shJARID1B (E) or their control cells. IgG was used as negative control (D and E, left). “Percentage of input” indicates the ratio of DNA fragment of each promoter region bound by H3K4me3 to the total amount of input DNA fragment without H3K4me3 antibody pull-down. **, P < 0.01 is based on the Student t test. All results are from three independent experiments. Error bars, SD.

Mentions: On the basis of the indispensable role of PTEN in the biologic functions of JARID1B, we overexpressed PTEN in HepG2-pBabe-JARID1B cells (Figure 8A) and silenced PTEN in SK-Hep1-pSuper-shJARID1B cells (Figure 8E). Of note, PTEN overexpression significantly decreased phosphorylation of P13K and Akt in HepG2-pBabe-JARID1B cells (Figure 8B). Moreover PTEN overexpression significantly decreased the proliferation (Figure 8C) as well as migration, invasion of HepG2-pBabe-JARID1B cells (Figure 8D), and EMT markers changes (Supplemental Figure 6C). Meanwhile silencing PTEN increased phosphorylation of P13K and AKT in SK-Hep1-pSuper-shJARID1B cells (Figure 8F). Moreover silencing PTEN in SK-Hep1-pSuper-shJARID1B cells significantly increased the proliferation (Figure 8G) as well as migration, invasion (Figure 8H), and EMT markers changes (Supplemental Figure 6D). Taken together, these results show that PTEN mediates JARID1B-induced EMT, migration and invasion in hepatocellular carcinoma cells.


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

Tang B, Qi G, Tang F, Yuan S, Wang Z, Liang X, Li B, Yu S, Liu J, Huang Q, Wei Y, Zhai R, Lei B, Yu H, Jiao X, He S - Oncotarget (2015)

JARID1B regulates PTEN transcriptional expression through H3K4 trimethylationA and B, the abundance of H3 lysine methylation was assessed in HCC cells with JARID1B overexpression (A) or silencing (B) by Western blotting using whole-cell lysate; total H3 and β-actin were used as a loading control. C, schematic presentation of three regions relative to the PTEN transcriptional start site used as primers to test histone occupied abundance. D and E, qChIP was performed to assess H3K4me3 occupancy in HepG2-pBabe-JARID1B (D), SK-Hep1-pSuper-shJARID1B (E) or their control cells. IgG was used as negative control (D and E, left). “Percentage of input” indicates the ratio of DNA fragment of each promoter region bound by H3K4me3 to the total amount of input DNA fragment without H3K4me3 antibody pull-down. **, P < 0.01 is based on the Student t test. All results are from three independent experiments. Error bars, SD.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4494969&req=5

Figure 8: JARID1B regulates PTEN transcriptional expression through H3K4 trimethylationA and B, the abundance of H3 lysine methylation was assessed in HCC cells with JARID1B overexpression (A) or silencing (B) by Western blotting using whole-cell lysate; total H3 and β-actin were used as a loading control. C, schematic presentation of three regions relative to the PTEN transcriptional start site used as primers to test histone occupied abundance. D and E, qChIP was performed to assess H3K4me3 occupancy in HepG2-pBabe-JARID1B (D), SK-Hep1-pSuper-shJARID1B (E) or their control cells. IgG was used as negative control (D and E, left). “Percentage of input” indicates the ratio of DNA fragment of each promoter region bound by H3K4me3 to the total amount of input DNA fragment without H3K4me3 antibody pull-down. **, P < 0.01 is based on the Student t test. All results are from three independent experiments. Error bars, SD.
Mentions: On the basis of the indispensable role of PTEN in the biologic functions of JARID1B, we overexpressed PTEN in HepG2-pBabe-JARID1B cells (Figure 8A) and silenced PTEN in SK-Hep1-pSuper-shJARID1B cells (Figure 8E). Of note, PTEN overexpression significantly decreased phosphorylation of P13K and Akt in HepG2-pBabe-JARID1B cells (Figure 8B). Moreover PTEN overexpression significantly decreased the proliferation (Figure 8C) as well as migration, invasion of HepG2-pBabe-JARID1B cells (Figure 8D), and EMT markers changes (Supplemental Figure 6C). Meanwhile silencing PTEN increased phosphorylation of P13K and AKT in SK-Hep1-pSuper-shJARID1B cells (Figure 8F). Moreover silencing PTEN in SK-Hep1-pSuper-shJARID1B cells significantly increased the proliferation (Figure 8G) as well as migration, invasion (Figure 8H), and EMT markers changes (Supplemental Figure 6D). Taken together, these results show that PTEN mediates JARID1B-induced EMT, migration and invasion in hepatocellular carcinoma cells.

Bottom Line: In addition Kaplan-Meier survival analysis showed that high expression of JARID1B was associated with decreased overall survival of HCC patients.Mechanistically, we found JARID1B exerts its function through modulation of H3K4me3 at the PTEN gene promoter, which was associated with inactive PTEN transcription.Our results, for the first time, portray a pivotal role of JARID1B in stimulating metastatic behaviors of HCC cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Hepatobiliary Surgery, Guilin Medical University, Affiliated Hospital, Guilin, Guangxi, People's Republic of China.

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.

No MeSH data available.


Related in: MedlinePlus