title: Embryonic NANOG activity defines colorectal cancer stem cells and modulates through AP1- and TCF-dependent mechanisms.
abstract: Embryonic NANOG (NANOG1) is considered as an important regulator of pluripotency while NANOGP8 (NANOG-pseudogene) plays a role in tumorigenesis. Herein, we show NANOG is expressed from both NANOG1 and NANOGP8 in human colorectal cancers (CRC). Enforced NANOG1-expression increases clonogenic potential and tumor formation in xenograft models, although it is expressed only in a small subpopulation of tumor cells and is colocalized with endogenous nuclear β-catenin(High) . Moreover, single NANOG1-CRCs form spherical aggregates, similar to the embryoid body of embryonic stem cells (ESCs), and express higher levels of stem-like Wnt-associated target genes. Furthermore, we show that NANOG1-expression is positively regulated by c-JUN and β-catenin/TCF4. Ectopic expression of c-Jun in murine Apc(Min/+) -ESCs results in the development of larger xenograft tumors with higher cell density compared to controls. Chromatin immunoprecipitation assays demonstrate that c-JUN binds to the NANOG1-promoter via the octamer M1 DNA element. Collectively, our data suggest that β-Catenin/TCF4 and c-JUN together drive a subpopulation of CRC tumor cells that adopt a stem-like phenotype via the NANOG1-promoter.
authors.affiliation: Cancer Genetics and Stem Cell Group, Division of Pre-Clinical Oncology, University of Nottingham, Nottingham, UK.
authors.forename: Elsayed E
authors.initials: EE
authors.lastname: Ibrahim
authors.forename: Roya
authors.initials: R
authors.lastname: Babaei-Jadidi
authors.forename: Anas
authors.initials: A
authors.lastname: Saadeddin
authors.forename: Bradley
authors.initials: B
authors.lastname: Spencer-Dene
authors.forename: Sina
authors.initials: S
authors.lastname: Hossaini
authors.forename: Mohammed
authors.initials: M
authors.lastname: Abuzinadah
authors.forename: Ningning
authors.initials: N
authors.lastname: Li
authors.forename: Wakkas
authors.initials: W
authors.lastname: Fadhil
authors.forename: Mohammad
authors.initials: M
authors.lastname: Ilyas
authors.forename: Dominique
authors.initials: D
authors.lastname: Bonnet
authors.forename: Abdolrahman S
authors.initials: AS
authors.lastname: Nateri
mesh_terms: D033961:Adaptor Protein Complex 1 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D002471:Cell Transformation, Neoplastic; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D000071317:Nanog Homeobox Protein; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011544:Pseudogenes; D015398:Signal Transduction / Q000235:genetics; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics
chemical_list: D033961:Adaptor Protein Complex 1; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C495270:CTNNB1 protein, human; D018398:Homeodomain Proteins; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin; D048031:JNK Mitogen-Activated Protein Kinases