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, Jan Jong Hung

Research output: Contribution to journalArticle

41 Citations (Scopus)

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 G 2/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.

Original languageEnglish
Pages (from-to)1115-1128
Number of pages14
JournalMolecular Pharmacology
Volume82
Issue number6
DOIs
Publication statusPublished - Dec 2012

Fingerprint

Sumoylation
Lung Neoplasms
Growth
Proteins
Cyclin A2
Proteolysis
SUMO-1 Protein
G2 Phase Cell Cycle Checkpoints
betulinic acid
Neoplasms
Retinoblastoma Protein
Ubiquitin-Protein Ligases
Phase Transition
Ubiquitin
HeLa Cells
Transcriptome
Heterografts
Cell Division
Genes
Cell Cycle

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine

Cite this

Betulinic acid decreases specificity protein 1 (Sp1) level via increasing the sumoylation of Sp1 to inhibit lung cancer growth. / Hsu, Tsung I.; Wang, Mei Chun; Chen, Szu Yu; Huang, Shih Ting; Yeh, Yu Min; Su, Wu Chou; Chang, Wen Chang; Hung, Jan Jong.

In: Molecular Pharmacology, Vol. 82, No. 6, 12.2012, p. 1115-1128.

Research output: Contribution to journalArticle

Hsu, Tsung I. ; Wang, Mei Chun ; Chen, Szu Yu ; Huang, Shih Ting ; Yeh, Yu Min ; Su, Wu Chou ; Chang, Wen Chang ; Hung, Jan Jong. / Betulinic acid decreases specificity protein 1 (Sp1) level via increasing the sumoylation of Sp1 to inhibit lung cancer growth. In: Molecular Pharmacology. 2012 ; Vol. 82, No. 6. pp. 1115-1128.
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