title: Epigenetic silencing of beta-spectrin, a TGF-beta signaling/scaffolding protein in a human cancer stem cell disorder: Beckwith-Wiedemann syndrome.
abstract: Hereditary cancer syndromes provide powerful insights into dysfunctional signaling pathways that lead to sporadic cancers. Beckwith-Wiedemann syndrome (BWS) is a hereditary human cancer stem cell syndrome currently linked to deregulated imprinting at chromosome 11p15 and uniparental disomy. However, causal molecular defects and genetic models have remained elusive to date in the majority of cases. The non-pleckstrin homology domain β-spectrin (β2SP) (the official name for human is Spectrin, beta, nonerythrocytic 1 (SPTBN1), isoform 2; the official name for mouse is Spectrin beta 2 (Spnb2), isoform 2), a scaffolding protein, functions as a potent TGF-β signaling member adaptor in tumor suppression and development. Yet, the role of the β2SP in human tumor syndromes remains unclear. Here, we report that β2SP(+/-) mice are born with many phenotypic characteristics observed in BWS patients, suggesting that β2SP mutant mice phenocopy BWS, and β2SP loss could be one of the mechanisms associated with BWS. Our results also suggest that epigenetic silencing of β2SP is a new potential causal factor in human BWS patients. Furthermore, β2SP(+/-) mice provide an important animal model for BWS, as well as sporadic cancers associated with it, including lethal gastrointestinal and pancreatic cancer. Thus, these studies could lead to further insight into defects generated by dysfunctional stem cells and identification of new treatment strategies and functional markers for the early detection of these lethal cancers that otherwise cannot be detected at an early stage.
authors.affiliation: Department of Gastroenterology, MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Zhi-Xing
authors.initials: ZX
authors.lastname: Yao
authors.forename: Wilma
authors.initials: W
authors.lastname: Jogunoori
authors.forename: Sanaa
authors.initials: S
authors.lastname: Choufani
authors.forename: Asif
authors.initials: A
authors.lastname: Rashid
authors.forename: Tiffany
authors.initials: T
authors.lastname: Blake
authors.forename: Wenguo
authors.initials: W
authors.lastname: Yao
authors.forename: Peter
authors.initials: P
authors.lastname: Kreishman
authors.forename: Rupen
authors.initials: R
authors.lastname: Amin
authors.forename: Anton A
authors.initials: AA
authors.lastname: Sidawy
authors.forename: Stephen R T
authors.initials: SR
authors.lastname: Evans
authors.forename: Milton
authors.initials: M
authors.lastname: Finegold
authors.forename: E Premkumar
authors.initials: EP
authors.lastname: Reddy
authors.forename: Bibhuti
authors.initials: B
authors.lastname: Mishra
authors.forename: Rosanna
authors.initials: R
authors.lastname: Weksberg
authors.forename: Rakesh
authors.initials: R
authors.lastname: Kumar
authors.forename: Lopa
authors.initials: L
authors.lastname: Mishra
mesh_terms: D000818:Animals; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D001483:Base Sequence; D001506:Beckwith-Wiedemann Syndrome / Q000235:genetics*; D015153:Blotting, Western; D019175:DNA Methylation / Q000187:drug effects; D000077209:Decitabine; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044127:Epigenesis, Genetic; D057890:Epigenomics; D020869:Gene Expression Profiling; D056945:Hep G2 Cells; D006579:Heterozygote; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000235:genetics; D013049:Spectrin / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D004791:Enzyme Inhibitors; C035170:IGF2 protein, human; C513121:IGF2 protein, mouse; D013049:Spectrin; D007335:Insulin-Like Growth Factor II; D000077209:Decitabine; D001374:Azacitidine