title: Histone demethylase KDM4C regulates sphere formation by mediating the cross talk between Wnt and Notch pathways in colonic cancer cells.
abstract: Alterations in genes coding for histone modifiers are found in human cancers, suggesting that histone modification is involved in malignant features of neoplastic cells. This study showed that a histone demethylase KDM4C is significant for colonosphere formation by mediating the cross talk between oncogenic pathways through a feed-forward mechanism. The expression of KDM4C gene was increased in spheres from colorectal cancer (CRC) cells and the knockdown (KD) of KDM4C eliminated colonosphere formation. We found that the KD of β-catenin, an important oncogenic factor in CRC, resulted in not only decreased sphere formation but also impaired upregulation of KDM4C gene in spheres. β-Catenin bound to the KDM4C promoter, suggesting that KDM4C is involved in the sphere-forming ability downstream of β-catenin in CRC cells. Microarray analysis identified the JAG1 gene that codes for a notch ligand Jagged1 responsible for sphere formation as a target of KDM4C. KDM4C KD decreased the expression of JAG1 gene, and the downregulation of JAG1 gene recapitulated the impaired colonosphere formation. JAG1 is also a target of β-catenin, and chromatin immunoprecipitation analysis showed the binding of β-catenin and KDM4C onto the JAG1 promoter during colonosphere formation. Importantly, KDM4C KD ruined the recruitment of β-catenin onto the JAG1 promoter independently of the H3-K9 methylation status and blunted JAG1 expression during sphere formation. These data indicate that KDM4C maintains the sphere-forming capacity in CRCs by mediating the β-catenin-dependent transcription of JAG1 in a feed-forward manner.
authors.affiliation: Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Shinzo
authors.initials: S
authors.lastname: Yamamoto
authors.forename: Keisuke
authors.initials: K
authors.lastname: Tateishi
authors.forename: Yotaro
authors.initials: Y
authors.lastname: Kudo
authors.forename: Keisuke
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Takayuki
authors.initials: T
authors.lastname: Isagawa
authors.forename: Genta
authors.initials: G
authors.lastname: Nagae
authors.forename: Takuma
authors.initials: T
authors.lastname: Nakatsuka
authors.forename: Yoshinari
authors.initials: Y
authors.lastname: Asaoka
authors.forename: Hideaki
authors.initials: H
authors.lastname: Ijichi
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Hirata
authors.forename: Motoyuki
authors.initials: M
authors.lastname: Otsuka
authors.forename: Tsuneo
authors.initials: T
authors.lastname: Ikenoue
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Aburatani
authors.forename: Masao
authors.initials: M
authors.lastname: Omata
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Koike
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D064593:Heterografts; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D000072100:Jagged-1 Protein; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics* / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D051880:Receptors, Notch / Q000378:metabolism*; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction; D018874:Spheroids, Cellular; D047368:Tumor Burden / Q000235:genetics; D014407:Tumor Cells, Cultured; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; C413655:KDM4C protein, human; D008565:Membrane Proteins; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; D051153:Wnt Proteins; D051176:beta Catenin; D056484:Jumonji Domain-Containing Histone Demethylases