Sustained activation of SMAD3/SMAD4 by FOXM1 promotes TGF-β-dependent cancer metastasis

Jianfei Xue, Xia Lin, Wen Tai Chiu, Yao Hui Chen, Guanzhen Yu, Mingguang Liu, Xin Hua Feng, Raymond Sawaya, René H. Medema, Mien Chie Hung, Suyun Huang

Research output: Contribution to journalArticle

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Abstract

A key feature of TGF-β signaling activation in cancer cells is the sustained activation of SMAD complexes in the nucleus; however, the drivers of SMAD activation are poorly defined. Here, using human and mouse breast cancer cell lines, we found that oncogene forkhead box M1 (FOXM1) interacts with SMAD3 to sustain activation of the SMAD3/SMAD4 complex in the nucleus. FOXM1 prevented the E3 ubiquitin-protein ligase transcriptional intermediary factor 1 γ (TIF1γ) from binding SMAD3 and monoubiquitinating SMAD4, which stabilized the SMAD3/SMAD4 complex. Loss of FOXM1 abolished TGF-β-induced SMAD3/SMAD4 formation. Moreover, the interaction of FOXM1 and SMAD3 promoted TGF-β/SMAD3-mediated transcriptional activity and target gene expression. We found that FOXM1/SMAD3 interaction was required for TGF-β-induced breast cancer invasion, which was the result of SMAD3/SMAD4-dependent upregulation of the transcription factor SLUG. Importantly, the function of FOXM1 in TGF-β-induced invasion was not dependent on FOXM1's transcriptional activity. Knockdown of SMAD3 diminished FOXM1-induced metastasis. Furthermore, FOXM1 levels correlated with activated TGF-β signaling and metastasis in human breast cancer specimens. Together, our data indicate that FOXM1 promotes breast cancer metastasis by increasing nuclear retention of SMAD3 and identify crosstalk between FOXM1 and TGF-β/SMAD3 pathways. This study highlights the critical interaction of FOXM1 and SMAD3 for controlling TGF-β signaling during metastasis.

Original languageEnglish
Pages (from-to)564-579
Number of pages16
JournalJournal of Clinical Investigation
Volume124
Issue number2
DOIs
Publication statusPublished - 2014 Feb 3

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Breast Neoplasms
Neoplasm Metastasis
Neoplasms
Ubiquitin-Protein Ligases
Oncogenes
Transcription Factors
Up-Regulation
Gene Expression
Cell Line
transcriptional intermediary factor 1

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Xue, Jianfei ; Lin, Xia ; Chiu, Wen Tai ; Chen, Yao Hui ; Yu, Guanzhen ; Liu, Mingguang ; Feng, Xin Hua ; Sawaya, Raymond ; Medema, René H. ; Hung, Mien Chie ; Huang, Suyun. / Sustained activation of SMAD3/SMAD4 by FOXM1 promotes TGF-β-dependent cancer metastasis. In: Journal of Clinical Investigation. 2014 ; Vol. 124, No. 2. pp. 564-579.
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title = "Sustained activation of SMAD3/SMAD4 by FOXM1 promotes TGF-β-dependent cancer metastasis",
abstract = "A key feature of TGF-β signaling activation in cancer cells is the sustained activation of SMAD complexes in the nucleus; however, the drivers of SMAD activation are poorly defined. Here, using human and mouse breast cancer cell lines, we found that oncogene forkhead box M1 (FOXM1) interacts with SMAD3 to sustain activation of the SMAD3/SMAD4 complex in the nucleus. FOXM1 prevented the E3 ubiquitin-protein ligase transcriptional intermediary factor 1 γ (TIF1γ) from binding SMAD3 and monoubiquitinating SMAD4, which stabilized the SMAD3/SMAD4 complex. Loss of FOXM1 abolished TGF-β-induced SMAD3/SMAD4 formation. Moreover, the interaction of FOXM1 and SMAD3 promoted TGF-β/SMAD3-mediated transcriptional activity and target gene expression. We found that FOXM1/SMAD3 interaction was required for TGF-β-induced breast cancer invasion, which was the result of SMAD3/SMAD4-dependent upregulation of the transcription factor SLUG. Importantly, the function of FOXM1 in TGF-β-induced invasion was not dependent on FOXM1's transcriptional activity. Knockdown of SMAD3 diminished FOXM1-induced metastasis. Furthermore, FOXM1 levels correlated with activated TGF-β signaling and metastasis in human breast cancer specimens. Together, our data indicate that FOXM1 promotes breast cancer metastasis by increasing nuclear retention of SMAD3 and identify crosstalk between FOXM1 and TGF-β/SMAD3 pathways. This study highlights the critical interaction of FOXM1 and SMAD3 for controlling TGF-β signaling during metastasis.",
author = "Jianfei Xue and Xia Lin and Chiu, {Wen Tai} and Chen, {Yao Hui} and Guanzhen Yu and Mingguang Liu and Feng, {Xin Hua} and Raymond Sawaya and Medema, {Ren{\'e} H.} and Hung, {Mien Chie} and Suyun Huang",
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Xue, J, Lin, X, Chiu, WT, Chen, YH, Yu, G, Liu, M, Feng, XH, Sawaya, R, Medema, RH, Hung, MC & Huang, S 2014, 'Sustained activation of SMAD3/SMAD4 by FOXM1 promotes TGF-β-dependent cancer metastasis', Journal of Clinical Investigation, vol. 124, no. 2, pp. 564-579. https://doi.org/10.1172/JCI71104

Sustained activation of SMAD3/SMAD4 by FOXM1 promotes TGF-β-dependent cancer metastasis. / Xue, Jianfei; Lin, Xia; Chiu, Wen Tai; Chen, Yao Hui; Yu, Guanzhen; Liu, Mingguang; Feng, Xin Hua; Sawaya, Raymond; Medema, René H.; Hung, Mien Chie; Huang, Suyun.

In: Journal of Clinical Investigation, Vol. 124, No. 2, 03.02.2014, p. 564-579.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Sustained activation of SMAD3/SMAD4 by FOXM1 promotes TGF-β-dependent cancer metastasis

AU - Xue, Jianfei

AU - Lin, Xia

AU - Chiu, Wen Tai

AU - Chen, Yao Hui

AU - Yu, Guanzhen

AU - Liu, Mingguang

AU - Feng, Xin Hua

AU - Sawaya, Raymond

AU - Medema, René H.

AU - Hung, Mien Chie

AU - Huang, Suyun

PY - 2014/2/3

Y1 - 2014/2/3

N2 - A key feature of TGF-β signaling activation in cancer cells is the sustained activation of SMAD complexes in the nucleus; however, the drivers of SMAD activation are poorly defined. Here, using human and mouse breast cancer cell lines, we found that oncogene forkhead box M1 (FOXM1) interacts with SMAD3 to sustain activation of the SMAD3/SMAD4 complex in the nucleus. FOXM1 prevented the E3 ubiquitin-protein ligase transcriptional intermediary factor 1 γ (TIF1γ) from binding SMAD3 and monoubiquitinating SMAD4, which stabilized the SMAD3/SMAD4 complex. Loss of FOXM1 abolished TGF-β-induced SMAD3/SMAD4 formation. Moreover, the interaction of FOXM1 and SMAD3 promoted TGF-β/SMAD3-mediated transcriptional activity and target gene expression. We found that FOXM1/SMAD3 interaction was required for TGF-β-induced breast cancer invasion, which was the result of SMAD3/SMAD4-dependent upregulation of the transcription factor SLUG. Importantly, the function of FOXM1 in TGF-β-induced invasion was not dependent on FOXM1's transcriptional activity. Knockdown of SMAD3 diminished FOXM1-induced metastasis. Furthermore, FOXM1 levels correlated with activated TGF-β signaling and metastasis in human breast cancer specimens. Together, our data indicate that FOXM1 promotes breast cancer metastasis by increasing nuclear retention of SMAD3 and identify crosstalk between FOXM1 and TGF-β/SMAD3 pathways. This study highlights the critical interaction of FOXM1 and SMAD3 for controlling TGF-β signaling during metastasis.

AB - A key feature of TGF-β signaling activation in cancer cells is the sustained activation of SMAD complexes in the nucleus; however, the drivers of SMAD activation are poorly defined. Here, using human and mouse breast cancer cell lines, we found that oncogene forkhead box M1 (FOXM1) interacts with SMAD3 to sustain activation of the SMAD3/SMAD4 complex in the nucleus. FOXM1 prevented the E3 ubiquitin-protein ligase transcriptional intermediary factor 1 γ (TIF1γ) from binding SMAD3 and monoubiquitinating SMAD4, which stabilized the SMAD3/SMAD4 complex. Loss of FOXM1 abolished TGF-β-induced SMAD3/SMAD4 formation. Moreover, the interaction of FOXM1 and SMAD3 promoted TGF-β/SMAD3-mediated transcriptional activity and target gene expression. We found that FOXM1/SMAD3 interaction was required for TGF-β-induced breast cancer invasion, which was the result of SMAD3/SMAD4-dependent upregulation of the transcription factor SLUG. Importantly, the function of FOXM1 in TGF-β-induced invasion was not dependent on FOXM1's transcriptional activity. Knockdown of SMAD3 diminished FOXM1-induced metastasis. Furthermore, FOXM1 levels correlated with activated TGF-β signaling and metastasis in human breast cancer specimens. Together, our data indicate that FOXM1 promotes breast cancer metastasis by increasing nuclear retention of SMAD3 and identify crosstalk between FOXM1 and TGF-β/SMAD3 pathways. This study highlights the critical interaction of FOXM1 and SMAD3 for controlling TGF-β signaling during metastasis.

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