TGF- beta / beta 2-spectrin/CTCF-regulated tumor suppression in human stem cell disorder Beckwith-Wiedemann syndrome

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. In this paper, the authors have reported that double-heterozygous Sptbn1 super( +/-) Smad3 super( +/-) mice, which have defective TGF- beta signaling, develop multiple tumors that are phenotypically similar to those of BWS patients. They further determined that chromatin insulator CCCTC-binding factor (CTCF) is TGF- beta inducible and facilitates TGF- beta -mediated repression of TERT transcription via interactions with beta 2SP and SMAD3. This regulation was abrogated in TGF- beta -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, they propose that loss of CTCF-dependent imprinting of tumor-promoting genes, such as IGF2 and TERT, results from a defective TGF- beta 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.