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Research ArticleArticle

Betulinic Acid Decreases Specificity Protein 1 (Sp1) Level via Increasing the Sumoylation of Sp1 to Inhibit Lung Cancer Growth

Tsung-I. Hsu, Mei-Chun Wang, Szu-Yu Chen, Shih-Ting Huang, Yu-Min Yeh, Wu-Chou Su, Wen-Chang Chang and Jan-Jong Hung
Molecular Pharmacology December 2012, 82 (6) 1115-1128; DOI: https://doi.org/10.1124/mol.112.078485
Tsung-I. Hsu
Institute of Basic Medical Sciences (T.-I.H.) and Department of Pharmacology (M.C.W., S.-T.H., W.-C.C., J.J.H.), College of Medicine, Institute of Bioinformatics and Biosignal Transduction, College of Bioscience and Biotechnology (S.-Y.C., W.-C.C., J.-J.H.), Department of Internal Medicine, College of Medicine (Y.-M.Y., W.-C.S.), and Center for Infectious Disease and Signal Transduction Research (W.-C.C., J.-J.H.), National Cheng Kung University, Tainan, Taiwan; and Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan (W.-C.C.)
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Mei-Chun Wang
Institute of Basic Medical Sciences (T.-I.H.) and Department of Pharmacology (M.C.W., S.-T.H., W.-C.C., J.J.H.), College of Medicine, Institute of Bioinformatics and Biosignal Transduction, College of Bioscience and Biotechnology (S.-Y.C., W.-C.C., J.-J.H.), Department of Internal Medicine, College of Medicine (Y.-M.Y., W.-C.S.), and Center for Infectious Disease and Signal Transduction Research (W.-C.C., J.-J.H.), National Cheng Kung University, Tainan, Taiwan; and Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan (W.-C.C.)
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Szu-Yu Chen
Institute of Basic Medical Sciences (T.-I.H.) and Department of Pharmacology (M.C.W., S.-T.H., W.-C.C., J.J.H.), College of Medicine, Institute of Bioinformatics and Biosignal Transduction, College of Bioscience and Biotechnology (S.-Y.C., W.-C.C., J.-J.H.), Department of Internal Medicine, College of Medicine (Y.-M.Y., W.-C.S.), and Center for Infectious Disease and Signal Transduction Research (W.-C.C., J.-J.H.), National Cheng Kung University, Tainan, Taiwan; and Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan (W.-C.C.)
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Shih-Ting Huang
Institute of Basic Medical Sciences (T.-I.H.) and Department of Pharmacology (M.C.W., S.-T.H., W.-C.C., J.J.H.), College of Medicine, Institute of Bioinformatics and Biosignal Transduction, College of Bioscience and Biotechnology (S.-Y.C., W.-C.C., J.-J.H.), Department of Internal Medicine, College of Medicine (Y.-M.Y., W.-C.S.), and Center for Infectious Disease and Signal Transduction Research (W.-C.C., J.-J.H.), National Cheng Kung University, Tainan, Taiwan; and Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan (W.-C.C.)
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Yu-Min Yeh
Institute of Basic Medical Sciences (T.-I.H.) and Department of Pharmacology (M.C.W., S.-T.H., W.-C.C., J.J.H.), College of Medicine, Institute of Bioinformatics and Biosignal Transduction, College of Bioscience and Biotechnology (S.-Y.C., W.-C.C., J.-J.H.), Department of Internal Medicine, College of Medicine (Y.-M.Y., W.-C.S.), and Center for Infectious Disease and Signal Transduction Research (W.-C.C., J.-J.H.), National Cheng Kung University, Tainan, Taiwan; and Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan (W.-C.C.)
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Wu-Chou Su
Institute of Basic Medical Sciences (T.-I.H.) and Department of Pharmacology (M.C.W., S.-T.H., W.-C.C., J.J.H.), College of Medicine, Institute of Bioinformatics and Biosignal Transduction, College of Bioscience and Biotechnology (S.-Y.C., W.-C.C., J.-J.H.), Department of Internal Medicine, College of Medicine (Y.-M.Y., W.-C.S.), and Center for Infectious Disease and Signal Transduction Research (W.-C.C., J.-J.H.), National Cheng Kung University, Tainan, Taiwan; and Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan (W.-C.C.)
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Wen-Chang Chang
Institute of Basic Medical Sciences (T.-I.H.) and Department of Pharmacology (M.C.W., S.-T.H., W.-C.C., J.J.H.), College of Medicine, Institute of Bioinformatics and Biosignal Transduction, College of Bioscience and Biotechnology (S.-Y.C., W.-C.C., J.-J.H.), Department of Internal Medicine, College of Medicine (Y.-M.Y., W.-C.S.), and Center for Infectious Disease and Signal Transduction Research (W.-C.C., J.-J.H.), National Cheng Kung University, Tainan, Taiwan; and Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan (W.-C.C.)
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Jan-Jong Hung
Institute of Basic Medical Sciences (T.-I.H.) and Department of Pharmacology (M.C.W., S.-T.H., W.-C.C., J.J.H.), College of Medicine, Institute of Bioinformatics and Biosignal Transduction, College of Bioscience and Biotechnology (S.-Y.C., W.-C.C., J.-J.H.), Department of Internal Medicine, College of Medicine (Y.-M.Y., W.-C.S.), and Center for Infectious Disease and Signal Transduction Research (W.-C.C., J.-J.H.), National Cheng Kung University, Tainan, Taiwan; and Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan (W.-C.C.)
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Abstract

Previous studies have shown that the inhibitory effect of betulinic acid (BA) on specificity protein 1 (Sp1) expression is involved in the prevention of cancer progression, but the mechanism of this effect remains to be delineated. In this study, we determined that BA treatment in HeLa cells increased the sumoylation of Sp1 by inhibiting sentrin-specific protease 1 expression. The subsequent recruitment of E3 ubiquitin-protein ligase RING finger protein 4 resulted in ubiquitin-mediated degradation in a 26S-proteosome-dependent pathway. In addition, both BA treatment and mithramycin A (MMA) treatment inhibited lung tumor growth and down-regulated Sp1 protein expression in KrasG12D-induced lung cancers of bitransgenic mice. In gene expression profiles of KrasG12D-induced lung cancers in bitransgenic mice with and without Sp1 inhibition, 542 genes were affected by MMA treatment. One of the gene products, cyclin A2, which was involved in the S and G2/M phase transition during cell cycle progression, was investigated in detail because its expression was regulated by Sp1. The down-regulation of cyclin A2 by BA treatment resulted in decreased retinoblastoma protein phosphorylation and cell cycle G2/M arrest. The BA-mediated cellular Sp1 degradation and antitumor effect were also confirmed in a xenograft mouse model by using H1299 cells. The knockdown of Sp1 in lung cancer cells attenuated the tumor-suppressive effect of BA. Taken together, the results of this study clarify the mechanism of BA-mediated Sp1 degradation and identify a pivotal role for Sp1 in the BA-induced repression of lung cancer growth.

Footnotes

  • ↵Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

  • This work was supported by the National Cheng-Kung University [project of the Program for Promoting Academic Excellence and Developing World Class Research Centers]; the National Science Council of Taiwan [Grants NSC 97-2320-B-038-039-MY3, NSC 100-2321-B-006-011-MY3, NSC 100-2320-B-038-032-MY3]; and the Department of Health, Executive Yuan of Taiwan [Grants DOH99-TD-B-111-002, DOH99-TD-B-111-003].

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    http://dx.doi.org/10.1124/mol.112.078485.

  • ABBREVIATIONS:

    NSCLC
    non-small cell lung cancer
    BA
    betulinic acid
    Sp1
    specificity protein 1
    MMA
    mithramycin A
    SUMO
    small ubiquitin-like modifier
    SENP1
    SUMO1/sentrin specific peptidase 1
    Rb
    retinoblastoma protein
    DMEM
    Dulbecco's modified Eagle's medium
    FBS
    fetal bovine serum
    DMSO
    dimethyl sulfoxide
    shRNA
    short hairpin RNA
    Scgb1a1
    secretoglobin, family 1A, member 1
    rtTA
    reverse tetracycline transactivator
    TetO
    tetracycline operator element
    PCR
    polymerase chain reaction
    HE
    hematoxylin-eosin
    PBS
    phosphate-buffered saline
    RT
    reverse transcription
    F
    forward
    R
    reverse
    PI
    propidium iodide
    GFP
    green fluorescent protein
    RIPA
    radioimmunoprecipitation assay
    RNF4
    RING finger protein 4
    PARP
    poly(ADP-ribose) polymerase
    Rpt6
    regulatory particle ATPase 6
    MTT
    3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium.

  • Received February 21, 2012.
  • Accepted September 5, 2012.
  • Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 82 (6)
Molecular Pharmacology
Vol. 82, Issue 6
1 Dec 2012
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Research ArticleArticle

Betulinic Acid Attenuates Sp1-Regulated CCNA2 in Lung Cancer

Tsung-I. Hsu, Mei-Chun Wang, Szu-Yu Chen, Shih-Ting Huang, Yu-Min Yeh, Wu-Chou Su, Wen-Chang Chang and Jan-Jong Hung
Molecular Pharmacology December 1, 2012, 82 (6) 1115-1128; DOI: https://doi.org/10.1124/mol.112.078485

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Research ArticleArticle

Betulinic Acid Attenuates Sp1-Regulated CCNA2 in Lung Cancer

Tsung-I. Hsu, Mei-Chun Wang, Szu-Yu Chen, Shih-Ting Huang, Yu-Min Yeh, Wu-Chou Su, Wen-Chang Chang and Jan-Jong Hung
Molecular Pharmacology December 1, 2012, 82 (6) 1115-1128; DOI: https://doi.org/10.1124/mol.112.078485
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