A TGF-β-CTCF regulated pathway suppresses stem cell associated tumor progression. TGF-β-CTCF regulated pathway

Beckwith-Wiedemann syndrome (BWS) is a human stem cell disorder with an 800-fold increase risk of developing tumors. Imprinting for the IGF2/H19 and the CDKN1C/KCNQ1 loci on chromosome 11p15.5 is mediated by the chromatin insulator CCCTC-binding factor (CTCF) and this regulation is lost in BWS, leading to aberrant overexpression of the growth promoting genes. Epigenetic silencing of β2-spectrin (β2SP, gene SPTBN1), a SMAD adaptor for Transforming Growth Factor-beta (TGF-β) signaling, is causally associated with BWS. Here we report that double heterozygous Sptbn1+/−/Smad3+/− mice with defective TGF-β pathway, developed multiple tumors phenotypically similar to those of BWS. Consistent with this, both the TGF-β defective mouse and patient BWS fibroblasts overexpress IGF2 and TERT. We further reveal CTCF is TGF-β-inducible and facilitates TGF-β-mediated repression of hTERT transcription via β2S/SMAD3/CTCF interactions. As such this regulation is abrogated in the TGF-β defective mice and BWS, causing hTERT overexpression. We propose the lifting of CTCF-dependent imprinting of tumor promoter genes such as IGF2 and TERT is caused by defective TGF-β pathway and responsible at least in part for BWS-associated tumorigenesis and human sporadic cancers frequently associated with mutations in SPTBN1 and SMAD3.