title: Epigenetic alteration of the NF-κB-inducing kinase (NIK) gene is involved in enhanced NIK expression in basal-like breast cancer.
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.
authors.affiliation: Department of Cancer Biology, Division of Cellular and Molecular Biology Laboratory of Stem Cell Therapy, Institute of Medical Science, University of Tokyo, Shirokane-dai, Minato-ku, Tokyo, Japan.
authors.forename: Mizuki
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Taku
authors.initials: T
authors.lastname: Ito
authors.forename: Takafumi
authors.initials: T
authors.lastname: Shimizu
authors.forename: Takaomi
authors.initials: T
authors.lastname: Ishida
authors.forename: Kentaro
authors.initials: K
authors.lastname: Semba
authors.forename: Shinya
authors.initials: S
authors.lastname: Watanabe
authors.forename: Noritaka
authors.initials: N
authors.lastname: Yamaguchi
authors.forename: Jun-Ichiro
authors.initials: J
authors.lastname: Inoue
mesh_terms: D000107:Acetylation / Q000187:drug effects; D001374:Azacitidine / Q000494:pharmacology; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics*; D006657:Histones / Q000378:metabolism; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D011960:Receptors, Estrogen / Q000235:genetics; D011980:Receptors, Progesterone / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014635:Valproic Acid / Q000494:pharmacology; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D001374:Azacitidine; D004791:Enzyme Inhibitors; D006657:Histones; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D014635:Valproic Acid; D000097782:NF-kappaB-Inducing Kinase; C508053:ERBB2 protein, human