Epigenetic alteration of the NF-κB-inducing kinase (NIK) gene is involved in enhanced NIK expression in basal-like breast cancer

Mizuki Yamamoto, Taku Ito, Takafumi Shimizu, Takaomi Ishida, Kentaro Senba, Shinya Watanabe, Noritaka Yamaguchi, Jun ichiro Inoue

    Research output: Contribution to journalArticle

    21 Citations (Scopus)

    Abstract

    Basal-like breast cancers are triple-negative (estrogen receptor negative, progesterone receptor negative, erythroblastic leukemia viral oncogene homolog 2 (ERBB2) negative) tumors with an aggressive clinical behavior that lacks effective molecular targets for therapy. We reported previously that the basal-like subtype cell lines display high constitutive nuclear factor (NF)-κB activation, whose inhibition in the basal-like subtypes suppressed their proliferation. Moreover, NF-κB-inducing kinase (NIK) is involved in the constitutive NF-κB activation. Here, we report that enhanced NIK expression, which is exclusively observed in the basal-like subtype rather than the luminal-like subtype or non-tumorigenic mammary epithelial cells, is caused by epigenetic alteration of the NIK gene. The stability of NIK mRNA and transcriptional activity driven by the NIK promoter are similar in the basal-like and luminal-like subtypes. However, histone H3 acetylation levels were up-regulated in the basal-like subtype. Furthermore, treatment of the luminal-like subtype with a histone deacetylase inhibitor, valproic acid, significantly increased NIK expression. Although DNA methylation of the NIK locus was not detected, NIK expression also increased when the luminal-like subtype was treated with 5-azacytidine, which inhibits histone H3-Lys-9 dimethylation in addition to DNA methylation. Taken together, these results suggest that the closed chromatin structure mediated by histone H3 methylation and deacetylation suppresses NIK expression in the luminal-like subtype, whereas disruption of these suppression mechanisms leads to enhanced NIK expression and the constitutive NF-κB activation in the basal-like subtype. Thus, NIK and genes induced by the NIK-mediated constitutive NF-κB activation could be therapeutic targets of basal-like breast cancer. (Cancer Sci 2010; 101: 2391-2397)

    Original languageEnglish
    Pages (from-to)2391-2397
    Number of pages7
    JournalCancer Science
    Volume101
    Issue number11
    DOIs
    Publication statusPublished - 2010 Nov

    Fingerprint

    Epigenomics
    Phosphotransferases
    Breast Neoplasms
    Genes
    Histones
    DNA Methylation
    Triple Negative Breast Neoplasms
    Azacitidine
    Histone Deacetylase Inhibitors
    Valproic Acid
    Progesterone Receptors
    Acetylation
    Oncogenes
    Estrogen Receptors
    Methylation
    Chromatin
    Neoplasms
    Leukemia
    Breast
    Epithelial Cells

    ASJC Scopus subject areas

    • Cancer Research
    • Oncology

    Cite this

    Epigenetic alteration of the NF-κB-inducing kinase (NIK) gene is involved in enhanced NIK expression in basal-like breast cancer. / Yamamoto, Mizuki; Ito, Taku; Shimizu, Takafumi; Ishida, Takaomi; Senba, Kentaro; Watanabe, Shinya; Yamaguchi, Noritaka; Inoue, Jun ichiro.

    In: Cancer Science, Vol. 101, No. 11, 11.2010, p. 2391-2397.

    Research output: Contribution to journalArticle

    Yamamoto, Mizuki ; Ito, Taku ; Shimizu, Takafumi ; Ishida, Takaomi ; Senba, Kentaro ; Watanabe, Shinya ; Yamaguchi, Noritaka ; Inoue, Jun ichiro. / Epigenetic alteration of the NF-κB-inducing kinase (NIK) gene is involved in enhanced NIK expression in basal-like breast cancer. In: Cancer Science. 2010 ; Vol. 101, No. 11. pp. 2391-2397.
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    abstract = "Basal-like breast cancers are triple-negative (estrogen receptor negative, progesterone receptor negative, erythroblastic leukemia viral oncogene homolog 2 (ERBB2) negative) tumors with an aggressive clinical behavior that lacks effective molecular targets for therapy. We reported previously that the basal-like subtype cell lines display high constitutive nuclear factor (NF)-κB activation, whose inhibition in the basal-like subtypes suppressed their proliferation. Moreover, NF-κB-inducing kinase (NIK) is involved in the constitutive NF-κB activation. Here, we report that enhanced NIK expression, which is exclusively observed in the basal-like subtype rather than the luminal-like subtype or non-tumorigenic mammary epithelial cells, is caused by epigenetic alteration of the NIK gene. The stability of NIK mRNA and transcriptional activity driven by the NIK promoter are similar in the basal-like and luminal-like subtypes. However, histone H3 acetylation levels were up-regulated in the basal-like subtype. Furthermore, treatment of the luminal-like subtype with a histone deacetylase inhibitor, valproic acid, significantly increased NIK expression. Although DNA methylation of the NIK locus was not detected, NIK expression also increased when the luminal-like subtype was treated with 5-azacytidine, which inhibits histone H3-Lys-9 dimethylation in addition to DNA methylation. Taken together, these results suggest that the closed chromatin structure mediated by histone H3 methylation and deacetylation suppresses NIK expression in the luminal-like subtype, whereas disruption of these suppression mechanisms leads to enhanced NIK expression and the constitutive NF-κB activation in the basal-like subtype. Thus, NIK and genes induced by the NIK-mediated constitutive NF-κB activation could be therapeutic targets of basal-like breast cancer. (Cancer Sci 2010; 101: 2391-2397)",
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    AU - Yamamoto, Mizuki

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    AU - Ishida, Takaomi

    AU - Senba, Kentaro

    AU - Watanabe, Shinya

    AU - Yamaguchi, Noritaka

    AU - Inoue, Jun ichiro

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    AB - Basal-like breast cancers are triple-negative (estrogen receptor negative, progesterone receptor negative, erythroblastic leukemia viral oncogene homolog 2 (ERBB2) negative) tumors with an aggressive clinical behavior that lacks effective molecular targets for therapy. We reported previously that the basal-like subtype cell lines display high constitutive nuclear factor (NF)-κB activation, whose inhibition in the basal-like subtypes suppressed their proliferation. Moreover, NF-κB-inducing kinase (NIK) is involved in the constitutive NF-κB activation. Here, we report that enhanced NIK expression, which is exclusively observed in the basal-like subtype rather than the luminal-like subtype or non-tumorigenic mammary epithelial cells, is caused by epigenetic alteration of the NIK gene. The stability of NIK mRNA and transcriptional activity driven by the NIK promoter are similar in the basal-like and luminal-like subtypes. However, histone H3 acetylation levels were up-regulated in the basal-like subtype. Furthermore, treatment of the luminal-like subtype with a histone deacetylase inhibitor, valproic acid, significantly increased NIK expression. Although DNA methylation of the NIK locus was not detected, NIK expression also increased when the luminal-like subtype was treated with 5-azacytidine, which inhibits histone H3-Lys-9 dimethylation in addition to DNA methylation. Taken together, these results suggest that the closed chromatin structure mediated by histone H3 methylation and deacetylation suppresses NIK expression in the luminal-like subtype, whereas disruption of these suppression mechanisms leads to enhanced NIK expression and the constitutive NF-κB activation in the basal-like subtype. Thus, NIK and genes induced by the NIK-mediated constitutive NF-κB activation could be therapeutic targets of basal-like breast cancer. (Cancer Sci 2010; 101: 2391-2397)

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