Transcription factors Sp1 and Sp3 regulate expression of human ABCG2 gene and chemoresistance phenotype
2013
Yang, W.J., Yonsei University College of Medicine, Seoul, Republic of Korea | Song, M.J., Yonsei University College of Medicine, Seoul, Republic of Korea | Park, E.Y., Sookmyung Womens University, Seoul, Republic of Korea | Lee, J.J., Yonsei University College of Medicine, Seoul, Republic of Korea | Park, J.H., Yonsei University College of Medicine, Seoul, Republic of Korea | Park, K.H., Yonsei University College of Medicine, Seoul, Republic of Korea | Park, J.H., Sookmyung Womens University, Seoul, Republic of Korea | Kim, H.P., Yonsei University College of Medicine, Seoul, Republic of Korea
ABCG2 is a member of the ATP binding cassette (ABC) transmembrane proteins that plays an important role in stem cell biology and drug resistance of cancer cells. In this study, we investigated how expression of human ABCG2 gene is regulated in lung cancer A549 cells. Binding of Sp1 and Sp3 transcription factors to the ABCG2 promoter in vitro and in vivo was elucidated by electrophoretic mobility shift assay and chromatin immunoprecipitation assay. The ABCG2 promoter activity was impaired when Sp1 sites were mutated but was enhanced by overexpression of Sp1 or Sp3 proteins. Knockdown of Sp1 or Sp3 expression by short interfering RNA significantly decreased the expression of ABCG2 mRNA and protein, resulting in attenuated formation of the side population in A549 cells. In addition, Sp1 inhibition in vivo by mithramycin A suppressed the percentage of the side population fraction and sphere forming activities of A549 cells. Moreover, inhibiting Sp1- or Sp3-dependent ABCG2 expression caused chemosensitization to the anticancer drug cisplatin. Collectively, our results demonstrate that Sp1 and Sp3 transcription factors are the primary determinants for activating basal transcription of the ABCG2 gene and play an important role in maintaining the side population phenotype of lung cancer cells.
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