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ZHX2 enhances the cytotoxicity of chemotherapeutic drugs in liver tumor cells by repressing MDR1 via interfering with NF-YA.

Ma H, Yue X, Gao L, Liang X, Yan W, Zhang Z, Shan H, Zhang H, Spear BT, Ma C - Oncotarget (2015)

Bottom Line: Consistently, elevated ZHX2 significantly reduced ADM efflux in HepG2 cells and greatly increased the CDDP-mediated suppression of liver tumor growth in vivo.Co-IP and ChIP assay further suggested that ZHX2 interacted with NF-YA and reduced NF-Y binding to the MDR1 promoter.Taken together, we clarify that ZHX2 represses NF-Y-mediated activation of MDR1 transcription and, in doing so, enhances the effects of chemotherapeutics in HCC cells both in vitro and in vivo.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, Shandong University School of Medicine, Jinan, Shandong, P.R. China.

ABSTRACT
We previously reported the tumor suppressor function of Zinc-fingers and homeoboxes 2 (ZHX2) in hepatocellular carcinoma (HCC). Other studies indicate the association of increased ZHX2 expression with improved response to high dose chemotherapy in multiple myeloma. Here, we aim to test whether increased ZHX2 levels in HCC cells repress multidrug resistance 1(MDR1) expression resulting in increased sensitivity to chemotherapeutic drugs. We showed evidence that increased ZHX2 levels correlated with reduced MDR1 expression and enhanced the cytotoxicity of CDDP and ADM in different HCC cell lines. Consistently, elevated ZHX2 significantly reduced ADM efflux in HepG2 cells and greatly increased the CDDP-mediated suppression of liver tumor growth in vivo. Furthermore, immunohistochemical staining demonstrated the inverse correlation of ZHX2 and MDR1 expression in HCC tissues. Luciferase report assay showed that ZHX2 repressed the MDR1 promoter activity, while knockdown of NF-YA or mutating the NF-Y binding site eliminated this ZHX2-mediated repression of MDR1 transcription. Co-IP and ChIP assay further suggested that ZHX2 interacted with NF-YA and reduced NF-Y binding to the MDR1 promoter. Taken together, we clarify that ZHX2 represses NF-Y-mediated activation of MDR1 transcription and, in doing so, enhances the effects of chemotherapeutics in HCC cells both in vitro and in vivo.

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Related in: MedlinePlus

ZHX2 expression is inverse correlated to the expression of MDR1 in HCCImmunohistochemical staining of ZHX2 and MDR1 in adjacent sections of cancer biopsies from 2 of the 30 HCC samples (upper panels, ZHX2 high and MDR1 low ; lower panels, ZHX2 low and MDR1 high). bars = 50μm; statistical results were shown in Table 1.
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Figure 1: ZHX2 expression is inverse correlated to the expression of MDR1 in HCCImmunohistochemical staining of ZHX2 and MDR1 in adjacent sections of cancer biopsies from 2 of the 30 HCC samples (upper panels, ZHX2 high and MDR1 low ; lower panels, ZHX2 low and MDR1 high). bars = 50μm; statistical results were shown in Table 1.

Mentions: We first evaluated the correlation of ZHX2 and MDR1 expression in HCC tissues. To address that, thirty HCC samples were involved to do immunohistochemical staining with antibodies against ZHX2 and MDR1. Consistent with our previous study [16], nucleic ZHX2 could be detected in less than 35% (9/30) involved HCC cases (F 1). Moreover, MDR1 expression in HCC tissue sections with nucleic ZHX2 was comparatively lower than that in HCC tissue sections without nucleic ZHX2 (Figure 1). Analysis results of Chi-square test and non-parametric test further confirmed the reverse correlation of nucleic ZHX2 with MDR1 in HCC (Table 1). Both the positive percentage (score of 4–12) and the expression intensity of nuclear ZHX2 (displayed as median ± SD) were significantly lower in MDR1-positive staining samples (score of 4–12) than that in MDR1-negative staining samples (p < 0.05). These indicated that reduced nuclear ZHX2 level might be responsible for enhanced MDR1 expression in HCC.


ZHX2 enhances the cytotoxicity of chemotherapeutic drugs in liver tumor cells by repressing MDR1 via interfering with NF-YA.

Ma H, Yue X, Gao L, Liang X, Yan W, Zhang Z, Shan H, Zhang H, Spear BT, Ma C - Oncotarget (2015)

ZHX2 expression is inverse correlated to the expression of MDR1 in HCCImmunohistochemical staining of ZHX2 and MDR1 in adjacent sections of cancer biopsies from 2 of the 30 HCC samples (upper panels, ZHX2 high and MDR1 low ; lower panels, ZHX2 low and MDR1 high). bars = 50μm; statistical results were shown in Table 1.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4359216&req=5

Figure 1: ZHX2 expression is inverse correlated to the expression of MDR1 in HCCImmunohistochemical staining of ZHX2 and MDR1 in adjacent sections of cancer biopsies from 2 of the 30 HCC samples (upper panels, ZHX2 high and MDR1 low ; lower panels, ZHX2 low and MDR1 high). bars = 50μm; statistical results were shown in Table 1.
Mentions: We first evaluated the correlation of ZHX2 and MDR1 expression in HCC tissues. To address that, thirty HCC samples were involved to do immunohistochemical staining with antibodies against ZHX2 and MDR1. Consistent with our previous study [16], nucleic ZHX2 could be detected in less than 35% (9/30) involved HCC cases (F 1). Moreover, MDR1 expression in HCC tissue sections with nucleic ZHX2 was comparatively lower than that in HCC tissue sections without nucleic ZHX2 (Figure 1). Analysis results of Chi-square test and non-parametric test further confirmed the reverse correlation of nucleic ZHX2 with MDR1 in HCC (Table 1). Both the positive percentage (score of 4–12) and the expression intensity of nuclear ZHX2 (displayed as median ± SD) were significantly lower in MDR1-positive staining samples (score of 4–12) than that in MDR1-negative staining samples (p < 0.05). These indicated that reduced nuclear ZHX2 level might be responsible for enhanced MDR1 expression in HCC.

Bottom Line: Consistently, elevated ZHX2 significantly reduced ADM efflux in HepG2 cells and greatly increased the CDDP-mediated suppression of liver tumor growth in vivo.Co-IP and ChIP assay further suggested that ZHX2 interacted with NF-YA and reduced NF-Y binding to the MDR1 promoter.Taken together, we clarify that ZHX2 represses NF-Y-mediated activation of MDR1 transcription and, in doing so, enhances the effects of chemotherapeutics in HCC cells both in vitro and in vivo.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, Shandong University School of Medicine, Jinan, Shandong, P.R. China.

ABSTRACT
We previously reported the tumor suppressor function of Zinc-fingers and homeoboxes 2 (ZHX2) in hepatocellular carcinoma (HCC). Other studies indicate the association of increased ZHX2 expression with improved response to high dose chemotherapy in multiple myeloma. Here, we aim to test whether increased ZHX2 levels in HCC cells repress multidrug resistance 1(MDR1) expression resulting in increased sensitivity to chemotherapeutic drugs. We showed evidence that increased ZHX2 levels correlated with reduced MDR1 expression and enhanced the cytotoxicity of CDDP and ADM in different HCC cell lines. Consistently, elevated ZHX2 significantly reduced ADM efflux in HepG2 cells and greatly increased the CDDP-mediated suppression of liver tumor growth in vivo. Furthermore, immunohistochemical staining demonstrated the inverse correlation of ZHX2 and MDR1 expression in HCC tissues. Luciferase report assay showed that ZHX2 repressed the MDR1 promoter activity, while knockdown of NF-YA or mutating the NF-Y binding site eliminated this ZHX2-mediated repression of MDR1 transcription. Co-IP and ChIP assay further suggested that ZHX2 interacted with NF-YA and reduced NF-Y binding to the MDR1 promoter. Taken together, we clarify that ZHX2 represses NF-Y-mediated activation of MDR1 transcription and, in doing so, enhances the effects of chemotherapeutics in HCC cells both in vitro and in vivo.

Show MeSH
Related in: MedlinePlus