| First Author | Chen J | Year | 2016 |
| Journal | J Clin Invest | Volume | 126 |
| Issue | 2 | Pages | 527-42 |
| PubMed ID | 26784546 | Mgi Jnum | J:231375 |
| Mgi Id | MGI:5770498 | Doi | 10.1172/JCI80937 |
| Citation | Chen J, et al. (2016) TGF-beta/beta2-spectrin/CTCF-regulated tumor suppression in human stem cell disorder Beckwith-Wiedemann syndrome. J Clin Invest 126(2):527-42 |
| abstractText | 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 beta2-spectrin (beta2SP, encoded by SPTBN1), a SMAD adaptor for TGF-beta signaling, is causally associated with BWS; however, a role of TGF-beta deficiency in BWS-associated neoplastic transformation is unexplored. Here, we have reported that double-heterozygous Sptbn1+/- Smad3+/- mice, which have defective TGF-beta 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-beta-defective mice. We 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 beta2SP 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, we 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. |
