TGF-β/β2-spectrin/CTCF-regulated tumor suppression in human stem cell disorder Beckwith-Wiedemann syndrome
Jian Chen, … , Hidekazu Tsukamoto, Lopa Mishra
Jian Chen, … , Hidekazu Tsukamoto, Lopa Mishra
Published February 1, 2016; First published January 19, 2016
Citation Information: J Clin Invest. 2016;126(2):527-542. https://doi.org/10.1172/JCI80937.
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Categories: Research Article Stem cells

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.

Authors

Jian Chen, Zhi-Xing Yao, Jiun-Sheng Chen, Young Jin Gi, Nina M. Muñoz, Suchin Kundra, H. Franklin Herlong, Yun Seong Jeong, Alexei Goltsov, Kazufumi Ohshiro, Nipun A. Mistry, Jianping Zhang, Xiaoping Su, Sanaa Choufani, Abhisek Mitra, Shulin Li, Bibhuti Mishra, Jon White, Asif Rashid, Alan Yaoqi Wang, Milind Javle, Marta Davila, Peter Michaely, Rosanna Weksberg, Wayne L. Hofstetter, Milton J. Finegold, Jerry W. Shay, Keigo Machida, Hidekazu Tsukamoto, Lopa Mishra

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Figure 1

Sptbn1+/– Smad3+/– mice develop multiple tumors and phenocopy features of BWS.

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Sptbn1+/– Smad3+/– mice develop multiple tumors and phenocopy features ...
(A) Tumor incidence in double Sptbn1+/– Smad3+/– (n = 15) and in single Sptbn1+/– (n = 43) and Smad3+/– (n = 30) mice. (B) Anterior linear ear lobe crease (red arrow) and frontal balding (pink arrow) are nontumorigenic hallmarks of BWS. Sptbn1+/– Smad3+/–mice spontaneously develop multiple primary cancers (black arrows) by 12 months of age, including (C) colon adenocarcinoma, (D) hepatocellular carcinoma, (E) small bowel adenocarcinoma, and (F) lung adenocarcinoma. Scale bars: 10 mm. (G) Enlargement of organs in Sptbn1+/– Smad3+/– mice at 4 months of age. Error bars are shown as SD. n = 3. *P < 0.05; **P < 0.01, 1-way ANOVA with post-hoc Bonferroni’s test. (H) H&E-stained sections reveal adrenal cytomegaly in the fetal adrenal cortex of mutant Sptbn1+/– Smad3+/– mice not seen in wild-type mice. The arrows point to an adrenal cortical cell with enlarged granular eosinophilic cytoplasm and large hyperchromatic nuclei in Sptbn1+/– Smad3+/– mice compared with wild-type mice. Scale bars: 25 μm; original magnification, ×60 (insets). (I) Somatic mutations in SPTBN1 and SMAD3 occur frequently in multiple human cancers. The contribution of tumor types (left panel) and the location of somatic mutations (right panel) were summarized on the basis of the data set from COSMIC. (J) The diagram shows that Sptbn1+/– Smad3+/– mice phenocopy features of BWS and develop multiple tumors.