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RUNX1, an androgen- and EZH2-regulated gene, has differential roles in AR-dependent and -independent prostate cancer.

Takayama K, Suzuki T, Tsutsumi S, Fujimura T, Urano T, Takahashi S, Homma Y, Aburatani H, Inoue S - Oncotarget (2015)

Bottom Line: We found RUNX1 is a target of AR and regulated positively by androgen.Repression of RUNX1 is important for the growth promotion ability of EZH2 in AR-independent cells.These results indicated the significance of RUNX1 for androgen-dependency and that loss of RUNX1 could be a key step for the progression of prostate cancer.

View Article: PubMed Central - PubMed

Affiliation: Department of Anti-Aging Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.

ABSTRACT
Androgen receptor (AR) signaling is essential for the development of prostate cancer. Here, we report that runt-related transcription factor (RUNX1) could be a key molecule for the androgen-dependence of prostate cancer. We found RUNX1 is a target of AR and regulated positively by androgen. Our RUNX1 ChIP-seq analysis indicated that RUNX1 is recruited to AR binding sites by interacting with AR. In androgen-dependent cancer, loss of RUNX1 impairs AR-dependent transcription and cell growth. The RUNX1 promoter is bound by enhancer of zeste homolog 2 (EZH2) and is negatively regulated by histone H3 lysine 27 (K27) trimethylation. Repression of RUNX1 is important for the growth promotion ability of EZH2 in AR-independent cells. In clinical prostate cancer samples, the RUNX1 expression level is negatively associated with EZH2 and that RUNX1 loss correlated with poor prognosis. These results indicated the significance of RUNX1 for androgen-dependency and that loss of RUNX1 could be a key step for the progression of prostate cancer.

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RUNX1 expression is negatively associated with EZH2 expression and loss of RUNX1 indicates a poor prognosis for prostate cancer patients(A) RUNX1 expression in prostate cancer. Immunohistochemistry (IHC) of RUNX1 in prostate cancer and benign prostate tissues (N = 103) was performed. Bar: 50 μm. (B) RUNX1 is a prognostic factor for prostate cancer patients. Kaplan-Meier analysis using the log-rank test was performed. (C) EZH2 is upregulated in prostate cancer. Immunohistochemistry of EZH2 in prostate cancer and benign prostate tissues (N = 103) was performed. Bar: 100 μm. (D) Negative correlation between RUNX1 and EZH2 expression levels. Regression analysis was performed to analyze the correlation. LI: labeling index. (E) Androgen-regulation of EZH2 in LNCaP cells. LNCaP cells were treated with vehicle or DHT for 24 h. Western blot analysis of EZH2 was performed. (F) Expression of EZH2 and RUNX1 in CRPC model cells. Protein expression of EZH2 and RUNX1 in LNCaP and CRPC model cells derived from LNCaP were analyzed by western blot analysis. (G) The role of RUNX1 in prostate cancer progression. RUNX1 promotes androgen-dependent prostate cancer cell proliferation by activating AR. However, in advanced prostate cancer, RUNX1 is downregulated epigenetically by EZH2. This repression would be correlated with another role of RUNX1 as a negative regulator of androgen-independent cell growth.
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Figure 6: RUNX1 expression is negatively associated with EZH2 expression and loss of RUNX1 indicates a poor prognosis for prostate cancer patients(A) RUNX1 expression in prostate cancer. Immunohistochemistry (IHC) of RUNX1 in prostate cancer and benign prostate tissues (N = 103) was performed. Bar: 50 μm. (B) RUNX1 is a prognostic factor for prostate cancer patients. Kaplan-Meier analysis using the log-rank test was performed. (C) EZH2 is upregulated in prostate cancer. Immunohistochemistry of EZH2 in prostate cancer and benign prostate tissues (N = 103) was performed. Bar: 100 μm. (D) Negative correlation between RUNX1 and EZH2 expression levels. Regression analysis was performed to analyze the correlation. LI: labeling index. (E) Androgen-regulation of EZH2 in LNCaP cells. LNCaP cells were treated with vehicle or DHT for 24 h. Western blot analysis of EZH2 was performed. (F) Expression of EZH2 and RUNX1 in CRPC model cells. Protein expression of EZH2 and RUNX1 in LNCaP and CRPC model cells derived from LNCaP were analyzed by western blot analysis. (G) The role of RUNX1 in prostate cancer progression. RUNX1 promotes androgen-dependent prostate cancer cell proliferation by activating AR. However, in advanced prostate cancer, RUNX1 is downregulated epigenetically by EZH2. This repression would be correlated with another role of RUNX1 as a negative regulator of androgen-independent cell growth.

Mentions: We performed immunohistochemical analysis to examine the protein levels of RUNX1 and EZH2 in clinical samples and to analyze the relationship between these factors (Fig.6A). In both prostate cancer and benign regions, RUNX1 is highly expressed in the nucleus, however, the labeling index (LI) of RUNX1 is decreased in prostate cancer tissues with a high Gleason score (Supplementary Table 1). Low RUNX1 expression in prostate cancer tissues was associated with poor cancer-specific survival of the patients (Fig.6B). In contrast, we observed strong expression of EZH2 in the nucleus of prostate cancer tissues, and weak expression in benign prostate tissues surrounding cancerous regions (Fig.6C). In addition, EZH2 expression is associated with poor prognosis of the patients (Supplementary Fig.5). Moreover, a strong negative correlation was observed between RUNX1 and EZH2 expression levels (R = −0.40, P < 0.0001, Fig.6D).


RUNX1, an androgen- and EZH2-regulated gene, has differential roles in AR-dependent and -independent prostate cancer.

Takayama K, Suzuki T, Tsutsumi S, Fujimura T, Urano T, Takahashi S, Homma Y, Aburatani H, Inoue S - Oncotarget (2015)

RUNX1 expression is negatively associated with EZH2 expression and loss of RUNX1 indicates a poor prognosis for prostate cancer patients(A) RUNX1 expression in prostate cancer. Immunohistochemistry (IHC) of RUNX1 in prostate cancer and benign prostate tissues (N = 103) was performed. Bar: 50 μm. (B) RUNX1 is a prognostic factor for prostate cancer patients. Kaplan-Meier analysis using the log-rank test was performed. (C) EZH2 is upregulated in prostate cancer. Immunohistochemistry of EZH2 in prostate cancer and benign prostate tissues (N = 103) was performed. Bar: 100 μm. (D) Negative correlation between RUNX1 and EZH2 expression levels. Regression analysis was performed to analyze the correlation. LI: labeling index. (E) Androgen-regulation of EZH2 in LNCaP cells. LNCaP cells were treated with vehicle or DHT for 24 h. Western blot analysis of EZH2 was performed. (F) Expression of EZH2 and RUNX1 in CRPC model cells. Protein expression of EZH2 and RUNX1 in LNCaP and CRPC model cells derived from LNCaP were analyzed by western blot analysis. (G) The role of RUNX1 in prostate cancer progression. RUNX1 promotes androgen-dependent prostate cancer cell proliferation by activating AR. However, in advanced prostate cancer, RUNX1 is downregulated epigenetically by EZH2. This repression would be correlated with another role of RUNX1 as a negative regulator of androgen-independent cell growth.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 6: RUNX1 expression is negatively associated with EZH2 expression and loss of RUNX1 indicates a poor prognosis for prostate cancer patients(A) RUNX1 expression in prostate cancer. Immunohistochemistry (IHC) of RUNX1 in prostate cancer and benign prostate tissues (N = 103) was performed. Bar: 50 μm. (B) RUNX1 is a prognostic factor for prostate cancer patients. Kaplan-Meier analysis using the log-rank test was performed. (C) EZH2 is upregulated in prostate cancer. Immunohistochemistry of EZH2 in prostate cancer and benign prostate tissues (N = 103) was performed. Bar: 100 μm. (D) Negative correlation between RUNX1 and EZH2 expression levels. Regression analysis was performed to analyze the correlation. LI: labeling index. (E) Androgen-regulation of EZH2 in LNCaP cells. LNCaP cells were treated with vehicle or DHT for 24 h. Western blot analysis of EZH2 was performed. (F) Expression of EZH2 and RUNX1 in CRPC model cells. Protein expression of EZH2 and RUNX1 in LNCaP and CRPC model cells derived from LNCaP were analyzed by western blot analysis. (G) The role of RUNX1 in prostate cancer progression. RUNX1 promotes androgen-dependent prostate cancer cell proliferation by activating AR. However, in advanced prostate cancer, RUNX1 is downregulated epigenetically by EZH2. This repression would be correlated with another role of RUNX1 as a negative regulator of androgen-independent cell growth.
Mentions: We performed immunohistochemical analysis to examine the protein levels of RUNX1 and EZH2 in clinical samples and to analyze the relationship between these factors (Fig.6A). In both prostate cancer and benign regions, RUNX1 is highly expressed in the nucleus, however, the labeling index (LI) of RUNX1 is decreased in prostate cancer tissues with a high Gleason score (Supplementary Table 1). Low RUNX1 expression in prostate cancer tissues was associated with poor cancer-specific survival of the patients (Fig.6B). In contrast, we observed strong expression of EZH2 in the nucleus of prostate cancer tissues, and weak expression in benign prostate tissues surrounding cancerous regions (Fig.6C). In addition, EZH2 expression is associated with poor prognosis of the patients (Supplementary Fig.5). Moreover, a strong negative correlation was observed between RUNX1 and EZH2 expression levels (R = −0.40, P < 0.0001, Fig.6D).

Bottom Line: We found RUNX1 is a target of AR and regulated positively by androgen.Repression of RUNX1 is important for the growth promotion ability of EZH2 in AR-independent cells.These results indicated the significance of RUNX1 for androgen-dependency and that loss of RUNX1 could be a key step for the progression of prostate cancer.

View Article: PubMed Central - PubMed

Affiliation: Department of Anti-Aging Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.

ABSTRACT
Androgen receptor (AR) signaling is essential for the development of prostate cancer. Here, we report that runt-related transcription factor (RUNX1) could be a key molecule for the androgen-dependence of prostate cancer. We found RUNX1 is a target of AR and regulated positively by androgen. Our RUNX1 ChIP-seq analysis indicated that RUNX1 is recruited to AR binding sites by interacting with AR. In androgen-dependent cancer, loss of RUNX1 impairs AR-dependent transcription and cell growth. The RUNX1 promoter is bound by enhancer of zeste homolog 2 (EZH2) and is negatively regulated by histone H3 lysine 27 (K27) trimethylation. Repression of RUNX1 is important for the growth promotion ability of EZH2 in AR-independent cells. In clinical prostate cancer samples, the RUNX1 expression level is negatively associated with EZH2 and that RUNX1 loss correlated with poor prognosis. These results indicated the significance of RUNX1 for androgen-dependency and that loss of RUNX1 could be a key step for the progression of prostate cancer.

Show MeSH
Related in: MedlinePlus