@article{508854d2b32044068e129c84a3bd5163,
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.",
author = "Jian Chen and Yao, {Zhi Xing} and Chen, {Jiun Sheng} and Gi, {Young Jin} and Mu{\~n}oz, {Nina M.} and Suchin Kundra and Herlong, {H. Franklin} and Jeong, {Yun Seong} and Alexei Goltsov and Kazufumi Ohshiro and Mistry, {Nipun A.} and Jianping Zhang and Xiaoping Su and Sanaa Choufani and Abhisek Mitra and Shulin Li and Bibhuti Mishra and Jon White and Asif Rashid and Wang, {Alan Yaoqi} and Milind Javle and Marta Davila and Peter Michaely and Rosanna Weksberg and Hofstetter, {Wayne L.} and Finegold, {Milton J.} and Shay, {Jerry W.} and Keigo Machida and Hidekazu Tsukamoto and Lopa Mishra",
note = "Funding Information: We thank Wilma S. Jogunoori, Sai-Ching Jim Yeung, Deborah Berry, Bhaskar V.S. Kallakury, and Shareen J. Iqbal for technical support. We also thank Waun Ki Hong, Robert C. Bast, and Eduardo M. Sotomayor for critical review and helpful comments on the manuscript. This research was supported by NIH grants R01CA106614 (to L. Mishra), R01CA042857 (to L. Mishra), R01AA023146 (to L. Mishra), P01 CA130821 (to L. Mishra), R01AA018857 (to K. Machida), RC2 AA019392 (to H. Tsukamoto and L. Mishra), P50AA011999 (to H. Tsukamoto), U01AA018663 (to H. Tsukamoto), RSG-12-177-01-MPC (to K. Machida), and IRG- 58-007-48 (to K. Machida). Funding was also received from the American Cancer Society (to K. Machida), the Medical Research Service of the Department of Veterans Affairs (to H. Tsukamoto), the University of Texas MD Anderson Multidisciplinary Research Program (to L. Mishra), Science & Technology Acquisition and Retention Funding (to L. Mishra), P30 DK56338 (to L. Mishra and Mary Estes), and P30 CA016672 (to L. Mishra and R. DePinho).",
year = "2016",
month = feb,
day = "1",
doi = "10.1172/JCI80937",
language = "English (US)",
volume = "126",
pages = "527--542",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "2",
}