title: Betulinic acid decreases specificity protein 1 (Sp1) level via increasing the sumoylation of sp1 to inhibit lung cancer growth.
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 Kras(G12D)-induced lung cancers of bitransgenic mice. In gene expression profiles of Kras(G12D)-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 G(2)/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.
authors.affiliation: Institute of Basic Medical Sciences, College of Medicine, Institute of Bioinformatics and Biosignal Transduction, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Tsung-I
authors.initials: TI
authors.lastname: Hsu
authors.forename: Mei-Chun
authors.initials: MC
authors.lastname: Wang
authors.forename: Szu-Yu
authors.initials: SY
authors.lastname: Chen
authors.forename: Shih-Ting
authors.initials: ST
authors.lastname: Huang
authors.forename: Yu-Min
authors.initials: YM
authors.lastname: Yeh
authors.forename: Wu-Chou
authors.initials: WC
authors.lastname: Su
authors.forename: Wen-Chang
authors.initials: WC
authors.lastname: Chang
authors.forename: Jan-Jong
authors.initials: JJ
authors.lastname: Hung
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000818:Animals; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D056751:Cyclin A2 / Q000235:genetics / Q000378:metabolism; D003546:Cysteine Endopeptidases; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism; D005260:Female; D006367:HeLa Cells; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D053978:Pentacyclic Triterpenes; D010766:Phosphorylation / Q000187:drug effects; D008926:Plicamycin / Q000031:analogs & derivatives / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism; D016329:Sp1 Transcription Factor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D058207:Sumoylation / Q000187:drug effects* / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome / Q000187:drug effects / Q000235:genetics; D014315:Triterpenes / Q000494:pharmacology*; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000094062:Betulinic Acid
chemical_list: C503721:CCNA2 protein, human; D056751:Cyclin A2; D009687:Nuclear Proteins; D053978:Pentacyclic Triterpenes; C114070:RNF4 protein, human; D016160:Retinoblastoma Protein; D016329:Sp1 Transcription Factor; D014157:Transcription Factors; D014315:Triterpenes; D025801:Ubiquitin; C066851:mithramycin A; D044767:Ubiquitin-Protein Ligases; D010450:Endopeptidases; C404512:SENP1 protein, human; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; D008926:Plicamycin; D000094062:Betulinic Acid