TGF-β/β2-spectrin/CTCF-regulated tumor suppression in human stem cell disorder Beckwith-Wiedemann syndrome

The Journal of Clinical Investigation
Jian ChenLopa Mishra

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 gen...Continue Reading

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Citations

Apr 4, 2016·Cancer Letters·L H KatzL Mishra
Jun 30, 2018·Journal of Computational Biology : a Journal of Computational Molecular Cell Biology·Jian-Xin WenYu Chang
Jul 18, 2018·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Jinqiang ZhangTong Wu
Jun 18, 2019·Journal of Cellular Physiology·Shuyi ChenXiuling Zhi
Dec 14, 2017·Genes & Cancer·Shoujun GuBibhuti Mishra
Feb 7, 2018·Hepatology Communications·Shuyun RaoLopa Mishra
Jan 24, 2017·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Jian ChenLopa Mishra
Dec 15, 2018·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Shuyun Rao, Lopa Mishra
Mar 21, 2019·American Journal of Medical Genetics. Part C, Seminars in Medical Genetics·Fei ChenYiping Shen
Apr 14, 2021·American Journal of Medical Genetics. Part a·Jill A RosenfeldBrendan H Lee
Nov 6, 2021·Biomarker Research·A Torres-Montaner
Nov 6, 2021·Cellular and Molecular Gastroenterology and Hepatology·Shuyi ChenXiuling Zhi

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Datasets Mentioned

BETA
GSE3228
GSE69737
GSE69752

Methods Mentioned

BETA
acetylation
PCR
transfection
nuclear translocation
ChIP
transgenic
immunoprecipitation
Assay
FACS
flow cytometry

Software Mentioned

DESeq
IPA

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