title: TGF-β/β2-spectrin/CTCF-regulated tumor suppression in human stem cell disorder Beckwith-Wiedemann syndrome.
abstract: Beckwith-Wiedemann syndrome (BWS) is a human stem cell disorder, and individuals with this disease have a substantially increased risk (~800-fold) of developing tumors. Epigenetic silencing of β2-spectrin (β2SP, encoded by SPTBN1), a SMAD adaptor for TGF-β signaling, is causally associated with BWS; however, a role of TGF-β deficiency in BWS-associated neoplastic transformation is unexplored. Here, we have reported that double-heterozygous Sptbn1+/- Smad3+/- mice, which have defective TGF-β signaling, develop multiple tumors that are phenotypically similar to those of BWS patients. Moreover, tumorigenesis-associated genes IGF2 and telomerase reverse transcriptase (TERT) were overexpressed in fibroblasts from BWS patients and TGF-β-defective mice. We further determined that chromatin insulator CCCTC-binding factor (CTCF) is TGF-β inducible and facilitates TGF-β-mediated repression of TERT transcription via interactions with β2SP and SMAD3. This regulation was abrogated in TGF-β-defective mice and BWS, resulting in TERT overexpression. Imprinting of the IGF2/H19 locus and the CDKN1C/KCNQ1 locus on chromosome 11p15.5 is mediated by CTCF, and this regulation is lost in BWS, leading to aberrant overexpression of growth-promoting genes. Therefore, we propose that loss of CTCF-dependent imprinting of tumor-promoting genes, such as IGF2 and TERT, results from a defective TGF-β pathway and is responsible at least in part for BWS-associated tumorigenesis as well as sporadic human cancers that are frequently associated with SPTBN1 and SMAD3 mutations.
authors.forename: Jian
authors.initials: J
authors.lastname: Chen
authors.forename: Zhi-Xing
authors.initials: ZX
authors.lastname: Yao
authors.forename: Jiun-Sheng
authors.initials: JS
authors.lastname: Chen
authors.forename: Young Jin
authors.initials: YJ
authors.lastname: Gi
authors.forename: Nina M
authors.initials: NM
authors.lastname: Muñoz
authors.forename: Suchin
authors.initials: S
authors.lastname: Kundra
authors.forename: H Franklin
authors.initials: HF
authors.lastname: Herlong
authors.forename: Yun Seong
authors.initials: YS
authors.lastname: Jeong
authors.forename: Alexei
authors.initials: A
authors.lastname: Goltsov
authors.forename: Kazufumi
authors.initials: K
authors.lastname: Ohshiro
authors.forename: Nipun A
authors.initials: NA
authors.lastname: Mistry
authors.forename: Jianping
authors.initials: J
authors.lastname: Zhang
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Su
authors.forename: Sanaa
authors.initials: S
authors.lastname: Choufani
authors.forename: Abhisek
authors.initials: A
authors.lastname: Mitra
authors.forename: Shulin
authors.initials: S
authors.lastname: Li
authors.forename: Bibhuti
authors.initials: B
authors.lastname: Mishra
authors.forename: Jon
authors.initials: J
authors.lastname: White
authors.forename: Asif
authors.initials: A
authors.lastname: Rashid
authors.forename: Alan Yaoqi
authors.initials: AY
authors.lastname: Wang
authors.forename: Milind
authors.initials: M
authors.lastname: Javle
authors.forename: Marta
authors.initials: M
authors.lastname: Davila
authors.forename: Peter
authors.initials: P
authors.lastname: Michaely
authors.forename: Rosanna
authors.initials: R
authors.lastname: Weksberg
authors.forename: Wayne L
authors.initials: WL
authors.lastname: Hofstetter
authors.forename: Milton J
authors.initials: MJ
authors.lastname: Finegold
authors.forename: Jerry W
authors.initials: JW
authors.lastname: Shay
authors.forename: Keigo
authors.initials: K
authors.lastname: Machida
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Tsukamoto
authors.forename: Lopa
authors.initials: L
authors.lastname: Mishra
mesh_terms: D000818:Animals; D001506:Beckwith-Wiedemann Syndrome / Q000235:genetics / Q000378:metabolism*; D000076246:CCCTC-Binding Factor; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics / Q000378:metabolism; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000235:genetics / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism; D051657:KCNQ1 Potassium Channel / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism; D019098:Telomerase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D013049:Spectrin
chemical_list: D000076246:CCCTC-Binding Factor; D002352:Carrier Proteins; D050761:Cyclin-Dependent Kinase Inhibitor p57; D007335:Insulin-Like Growth Factor II; D051657:KCNQ1 Potassium Channel; D008840:Microfilament Proteins; D009363:Neoplasm Proteins; D012097:Repressor Proteins; D051900:Smad3 Protein; D019098:Telomerase; D016212:Transforming Growth Factor beta; D013049:Spectrin; C493964:CDKN1C protein, human; C000619697:CTCF protein, human; C493965:Cdkn1c protein, mouse; C000619698:Ctcf protein, mouse; C035170:IGF2 protein, human; C513121:IGF2 protein, mouse; C496909:KCNQ1 protein, human; C496910:Kcnq1 protein, mouse; C497790:SMAD3 protein, human; C497791:Smad3 protein, mouse; C509186:TERT protein, human; C509187:Tert protein, mouse