Hypoxia-induced Slug SUMOylation enhances lung cancer metastasis 11 Medical and Health Sciences 1112 Oncology and Carcinogenesis 06 Biological Sciences 0601 Biochemistry and Cell Biology

Pei Fang Hung, Tse-Ming Hong, Che Chang Chang, Chung Lieh Hung, Yuan Ling Hsu, Yih Leong Chang, Chen Tu Wu, Gee Chen Chang, Nei Li Chan, Sung Liang Yu, Pan Chyr Yang, Szu Hua Pan

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Background: The Slug-E-cadherin axis plays a critical role in non-small-cell lung cancers (NSCLCs) where aberrant upregulation of Slug promotes cancer metastasis. Now, the post-translational modifications of Slug and their regulation mechanisms still remain unclear in lung cancer. Hence, exploring the protein linkage map of Slug is of great interest for investigating the scenario of how Slug protein is regulated in lung cancer metastasis. Methods: The Slug associated proteins, Ubc9 and SUMO-1, were identified using yeast two-hybrid screening; and in vitro SUMOylation assays combined with immunoprecipitation and immunoblotting were performed to explore the detail events and regulations of Slug SUMOylation. The functional effects of SUMOylation on Slug proteins were examined by EMSA, reporter assay, ChIP assay, RT-PCR, migration and invasion assays in vitro, tail vein metastatic analysis in vivo, and also evaluated the association with clinical outcome of NSCLC patients. Results: Slug protein could interact with Ubc9 and SUMO-1 and be SUMOylated in cells. Amino acids 130-212 and 33-129 of Slug are responsible for its binding to Ubc9 and protein inhibitor of activated STAT (PIAS)y, respectively. SUMOylation could enhance the transcriptional repression activity of Slug via recruiting more HDAC1, resulting in reduced expression of downstream Slug target genes and enhanced lung cancer metastasis. In addition, hypoxia could increase Slug SUMOylation through attenuating the interactions of Slug with SENP1 and SENP2. Finally, high expression Slug and Ubc9 levels were associated with poor overall survival among NSCLC patients. Conclusions: Ubc9/PIASy-mediated Slug SUMOylation and subsequent HDAC1 recruitment may play a crucial role in hypoxia-induced lung cancer progression, and these processes may serve as therapeutic targets for NSCLC.

Original languageEnglish
Article number5
JournalJournal of Experimental and Clinical Cancer Research
Volume38
Issue number1
DOIs
Publication statusPublished - 2019 Jan 6

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Sumoylation
Gastropoda
Biological Science Disciplines
Biochemistry
Cell Biology
Lung Neoplasms
Carcinogenesis
Neoplasm Metastasis
Health
Non-Small Cell Lung Carcinoma
Hypoxia
Protein Inhibitors of Activated STAT
SUMO-1 Protein
Proteins

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Hung, Pei Fang ; Hong, Tse-Ming ; Chang, Che Chang ; Hung, Chung Lieh ; Hsu, Yuan Ling ; Chang, Yih Leong ; Wu, Chen Tu ; Chang, Gee Chen ; Chan, Nei Li ; Yu, Sung Liang ; Yang, Pan Chyr ; Pan, Szu Hua. / Hypoxia-induced Slug SUMOylation enhances lung cancer metastasis 11 Medical and Health Sciences 1112 Oncology and Carcinogenesis 06 Biological Sciences 0601 Biochemistry and Cell Biology. In: Journal of Experimental and Clinical Cancer Research. 2019 ; Vol. 38, No. 1.
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title = "Hypoxia-induced Slug SUMOylation enhances lung cancer metastasis 11 Medical and Health Sciences 1112 Oncology and Carcinogenesis 06 Biological Sciences 0601 Biochemistry and Cell Biology",
abstract = "Background: The Slug-E-cadherin axis plays a critical role in non-small-cell lung cancers (NSCLCs) where aberrant upregulation of Slug promotes cancer metastasis. Now, the post-translational modifications of Slug and their regulation mechanisms still remain unclear in lung cancer. Hence, exploring the protein linkage map of Slug is of great interest for investigating the scenario of how Slug protein is regulated in lung cancer metastasis. Methods: The Slug associated proteins, Ubc9 and SUMO-1, were identified using yeast two-hybrid screening; and in vitro SUMOylation assays combined with immunoprecipitation and immunoblotting were performed to explore the detail events and regulations of Slug SUMOylation. The functional effects of SUMOylation on Slug proteins were examined by EMSA, reporter assay, ChIP assay, RT-PCR, migration and invasion assays in vitro, tail vein metastatic analysis in vivo, and also evaluated the association with clinical outcome of NSCLC patients. Results: Slug protein could interact with Ubc9 and SUMO-1 and be SUMOylated in cells. Amino acids 130-212 and 33-129 of Slug are responsible for its binding to Ubc9 and protein inhibitor of activated STAT (PIAS)y, respectively. SUMOylation could enhance the transcriptional repression activity of Slug via recruiting more HDAC1, resulting in reduced expression of downstream Slug target genes and enhanced lung cancer metastasis. In addition, hypoxia could increase Slug SUMOylation through attenuating the interactions of Slug with SENP1 and SENP2. Finally, high expression Slug and Ubc9 levels were associated with poor overall survival among NSCLC patients. Conclusions: Ubc9/PIASy-mediated Slug SUMOylation and subsequent HDAC1 recruitment may play a crucial role in hypoxia-induced lung cancer progression, and these processes may serve as therapeutic targets for NSCLC.",
author = "Hung, {Pei Fang} and Tse-Ming Hong and Chang, {Che Chang} and Hung, {Chung Lieh} and Hsu, {Yuan Ling} and Chang, {Yih Leong} and Wu, {Chen Tu} and Chang, {Gee Chen} and Chan, {Nei Li} and Yu, {Sung Liang} and Yang, {Pan Chyr} and Pan, {Szu Hua}",
year = "2019",
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doi = "10.1186/s13046-018-0996-8",
language = "English",
volume = "38",
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Hypoxia-induced Slug SUMOylation enhances lung cancer metastasis 11 Medical and Health Sciences 1112 Oncology and Carcinogenesis 06 Biological Sciences 0601 Biochemistry and Cell Biology. / Hung, Pei Fang; Hong, Tse-Ming; Chang, Che Chang; Hung, Chung Lieh; Hsu, Yuan Ling; Chang, Yih Leong; Wu, Chen Tu; Chang, Gee Chen; Chan, Nei Li; Yu, Sung Liang; Yang, Pan Chyr; Pan, Szu Hua.

In: Journal of Experimental and Clinical Cancer Research, Vol. 38, No. 1, 5, 06.01.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Hypoxia-induced Slug SUMOylation enhances lung cancer metastasis 11 Medical and Health Sciences 1112 Oncology and Carcinogenesis 06 Biological Sciences 0601 Biochemistry and Cell Biology

AU - Hung, Pei Fang

AU - Hong, Tse-Ming

AU - Chang, Che Chang

AU - Hung, Chung Lieh

AU - Hsu, Yuan Ling

AU - Chang, Yih Leong

AU - Wu, Chen Tu

AU - Chang, Gee Chen

AU - Chan, Nei Li

AU - Yu, Sung Liang

AU - Yang, Pan Chyr

AU - Pan, Szu Hua

PY - 2019/1/6

Y1 - 2019/1/6

N2 - Background: The Slug-E-cadherin axis plays a critical role in non-small-cell lung cancers (NSCLCs) where aberrant upregulation of Slug promotes cancer metastasis. Now, the post-translational modifications of Slug and their regulation mechanisms still remain unclear in lung cancer. Hence, exploring the protein linkage map of Slug is of great interest for investigating the scenario of how Slug protein is regulated in lung cancer metastasis. Methods: The Slug associated proteins, Ubc9 and SUMO-1, were identified using yeast two-hybrid screening; and in vitro SUMOylation assays combined with immunoprecipitation and immunoblotting were performed to explore the detail events and regulations of Slug SUMOylation. The functional effects of SUMOylation on Slug proteins were examined by EMSA, reporter assay, ChIP assay, RT-PCR, migration and invasion assays in vitro, tail vein metastatic analysis in vivo, and also evaluated the association with clinical outcome of NSCLC patients. Results: Slug protein could interact with Ubc9 and SUMO-1 and be SUMOylated in cells. Amino acids 130-212 and 33-129 of Slug are responsible for its binding to Ubc9 and protein inhibitor of activated STAT (PIAS)y, respectively. SUMOylation could enhance the transcriptional repression activity of Slug via recruiting more HDAC1, resulting in reduced expression of downstream Slug target genes and enhanced lung cancer metastasis. In addition, hypoxia could increase Slug SUMOylation through attenuating the interactions of Slug with SENP1 and SENP2. Finally, high expression Slug and Ubc9 levels were associated with poor overall survival among NSCLC patients. Conclusions: Ubc9/PIASy-mediated Slug SUMOylation and subsequent HDAC1 recruitment may play a crucial role in hypoxia-induced lung cancer progression, and these processes may serve as therapeutic targets for NSCLC.

AB - Background: The Slug-E-cadherin axis plays a critical role in non-small-cell lung cancers (NSCLCs) where aberrant upregulation of Slug promotes cancer metastasis. Now, the post-translational modifications of Slug and their regulation mechanisms still remain unclear in lung cancer. Hence, exploring the protein linkage map of Slug is of great interest for investigating the scenario of how Slug protein is regulated in lung cancer metastasis. Methods: The Slug associated proteins, Ubc9 and SUMO-1, were identified using yeast two-hybrid screening; and in vitro SUMOylation assays combined with immunoprecipitation and immunoblotting were performed to explore the detail events and regulations of Slug SUMOylation. The functional effects of SUMOylation on Slug proteins were examined by EMSA, reporter assay, ChIP assay, RT-PCR, migration and invasion assays in vitro, tail vein metastatic analysis in vivo, and also evaluated the association with clinical outcome of NSCLC patients. Results: Slug protein could interact with Ubc9 and SUMO-1 and be SUMOylated in cells. Amino acids 130-212 and 33-129 of Slug are responsible for its binding to Ubc9 and protein inhibitor of activated STAT (PIAS)y, respectively. SUMOylation could enhance the transcriptional repression activity of Slug via recruiting more HDAC1, resulting in reduced expression of downstream Slug target genes and enhanced lung cancer metastasis. In addition, hypoxia could increase Slug SUMOylation through attenuating the interactions of Slug with SENP1 and SENP2. Finally, high expression Slug and Ubc9 levels were associated with poor overall survival among NSCLC patients. Conclusions: Ubc9/PIASy-mediated Slug SUMOylation and subsequent HDAC1 recruitment may play a crucial role in hypoxia-induced lung cancer progression, and these processes may serve as therapeutic targets for NSCLC.

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U2 - 10.1186/s13046-018-0996-8

DO - 10.1186/s13046-018-0996-8

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