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

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 WangMilind Javle, Marta Davila, Peter Michaely, Rosanna Weksberg, Wayne L. Hofstetter, Milton J. Finegold, Jerry W. Shay, Keigo Machida, Hidekazu Tsukamoto, Lopa Mishra

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)527-542
Number of pages16
JournalJournal of Clinical Investigation
Volume126
Issue number2
DOIs
StatePublished - Feb 1 2016

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Beckwith-Wiedemann Syndrome
Spectrin
Chromatin
Stem Cells
Telomerase
Neoplasms
Carcinogenesis
Genes
CCCTC-binding factor
Epigenomics
Reverse Transcription
Fibroblasts
Chromosomes
Mutation

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Chen, J., Yao, Z. X., Chen, J. S., Gi, Y. J., Muñoz, N. M., Kundra, S., ... Mishra, L. (2016). TGF-β/β2-spectrin/CTCF-regulated tumor suppression in human stem cell disorder Beckwith-Wiedemann syndrome. Journal of Clinical Investigation, 126(2), 527-542. https://doi.org/10.1172/JCI80937

TGF-β/β2-spectrin/CTCF-regulated tumor suppression in human stem cell disorder Beckwith-Wiedemann syndrome. / Chen, Jian; Yao, Zhi Xing; Chen, Jiun Sheng; Gi, Young Jin; Muñoz, Nina M.; Kundra, Suchin; Herlong, H. Franklin; Jeong, Yun Seong; Goltsov, Alexei; Ohshiro, Kazufumi; Mistry, Nipun A.; Zhang, Jianping; Su, Xiaoping; Choufani, Sanaa; Mitra, Abhisek; Li, Shulin; Mishra, Bibhuti; White, Jon; Rashid, Asif; Wang, Alan Yaoqi; Javle, Milind; Davila, Marta; Michaely, Peter; Weksberg, Rosanna; Hofstetter, Wayne L.; Finegold, Milton J.; Shay, Jerry W.; Machida, Keigo; Tsukamoto, Hidekazu; Mishra, Lopa.

In: Journal of Clinical Investigation, Vol. 126, No. 2, 01.02.2016, p. 527-542.

Research output: Contribution to journalArticle

Chen, J, Yao, ZX, Chen, JS, Gi, YJ, Muñoz, NM, Kundra, S, Herlong, HF, Jeong, YS, Goltsov, A, Ohshiro, K, Mistry, NA, Zhang, J, Su, X, Choufani, S, Mitra, A, Li, S, Mishra, B, White, J, Rashid, A, Wang, AY, Javle, M, Davila, M, Michaely, P, Weksberg, R, Hofstetter, WL, Finegold, MJ, Shay, JW, Machida, K, Tsukamoto, H & Mishra, L 2016, 'TGF-β/β2-spectrin/CTCF-regulated tumor suppression in human stem cell disorder Beckwith-Wiedemann syndrome', Journal of Clinical Investigation, vol. 126, no. 2, pp. 527-542. https://doi.org/10.1172/JCI80937
Chen, Jian ; Yao, Zhi Xing ; Chen, Jiun Sheng ; Gi, Young Jin ; Muñoz, Nina M. ; Kundra, Suchin ; Herlong, H. Franklin ; Jeong, Yun Seong ; Goltsov, Alexei ; Ohshiro, Kazufumi ; Mistry, Nipun A. ; Zhang, Jianping ; Su, Xiaoping ; Choufani, Sanaa ; Mitra, Abhisek ; Li, Shulin ; Mishra, Bibhuti ; White, Jon ; Rashid, Asif ; Wang, Alan Yaoqi ; Javle, Milind ; Davila, Marta ; Michaely, Peter ; Weksberg, Rosanna ; Hofstetter, Wayne L. ; Finegold, Milton J. ; Shay, Jerry W. ; Machida, Keigo ; Tsukamoto, Hidekazu ; Mishra, Lopa. / TGF-β/β2-spectrin/CTCF-regulated tumor suppression in human stem cell disorder Beckwith-Wiedemann syndrome. In: Journal of Clinical Investigation. 2016 ; Vol. 126, No. 2. pp. 527-542.
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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.",
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AU - Chen, Jian

AU - Yao, Zhi Xing

AU - Chen, Jiun Sheng

AU - Gi, Young Jin

AU - Muñoz, Nina M.

AU - Kundra, Suchin

AU - Herlong, H. Franklin

AU - Jeong, Yun Seong

AU - Goltsov, Alexei

AU - Ohshiro, Kazufumi

AU - Mistry, Nipun A.

AU - Zhang, Jianping

AU - Su, Xiaoping

AU - Choufani, Sanaa

AU - Mitra, Abhisek

AU - Li, Shulin

AU - Mishra, Bibhuti

AU - White, Jon

AU - Rashid, Asif

AU - Wang, Alan Yaoqi

AU - Javle, Milind

AU - Davila, Marta

AU - Michaely, Peter

AU - Weksberg, Rosanna

AU - Hofstetter, Wayne L.

AU - Finegold, Milton J.

AU - Shay, Jerry W.

AU - Machida, Keigo

AU - Tsukamoto, Hidekazu

AU - Mishra, Lopa

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N2 - 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.

AB - 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.

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