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Transcription factors Sp1 and Sp3 regulate expression of human ABCG2 gene and chemoresistance phenotype

Wook-Jin Yang1, Min-Ji Song, Eun Young Park

  • 1Department of Environmental Medical Biology, Institute of Tropical Medicine, and Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, 120-752, Korea.

Molecules and Cells
|September 3, 2013
PubMed

Insights

Sp1 and Sp3 transcription factors activate ABCG2 gene expression in lung cancer cells. This regulation is crucial for maintaining cancer stem cell properties and drug resistance, offering potential therapeutic targets.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Genetics

Background:

  • ABCG2 (ATP-binding cassette subfamily G member 2) is a transmembrane protein vital in stem cell biology and cancer drug resistance.
  • Understanding ABCG2 gene regulation is key to developing effective lung cancer therapies.

Purpose of the Study:

  • To investigate the regulation of human ABCG2 gene expression in A549 lung cancer cells.
  • To identify the transcription factors involved in controlling ABCG2 promoter activity and its role in cancer stem cell phenotypes.

Main Methods:

  • Electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) to analyze Sp1 and Sp3 binding to the ABCG2 promoter.
  • Gene silencing using short interfering RNA (siRNA) to assess the impact of Sp1/Sp3 knockdown on ABCG2 expression.
  • In vivo studies using mithramycin A to inhibit Sp1 activity and assess effects on side population and sphere formation.

Main Results:

  • Sp1 and Sp3 transcription factors bind to the ABCG2 promoter both in vitro and in vivo.
  • Mutating Sp1 binding sites reduced ABCG2 promoter activity, while Sp1/Sp3 overexpression enhanced it.
  • Knockdown of Sp1 or Sp3 significantly decreased ABCG2 expression, reducing side population formation and sphere-forming capacity.
  • Sp1 inhibition suppressed side population and sphere formation, and sensitized cells to cisplatin.

Conclusions:

  • Sp1 and Sp3 are primary determinants activating basal transcription of the ABCG2 gene in lung cancer cells.
  • These factors play a critical role in maintaining the side population phenotype, associated with cancer stem cells.
  • Targeting Sp1/Sp3-mediated ABCG2 expression can enhance chemosensitivity to drugs like cisplatin, offering a potential therapeutic strategy.

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