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YY1 suppresses FEN1 over-expression and drug resistance in breast cancer

Jianwei Wang1, Lina Zhou2,3, Zhi Li4

  • 1College of Life Sciences, Zhejiang University, Hangzhou, China. lch1239wang@126.com.

BMC Cancer
|April 18, 2015
PubMed
Abstract

Insights

Transcription repressor YY1 regulates Flap endonuclease 1 (FEN1) expression, impacting cancer drug resistance. Higher FEN1 levels correlate with poorer survival in breast cancer patients, suggesting FEN1 as a therapeutic target.

Area of Science:

  • Molecular oncology and cancer therapeutics
  • DNA repair mechanisms and drug resistance

Background:

  • Drug resistance is a major hurdle in cancer therapy, often linked to enhanced DNA repair systems after chemotherapy.
  • Flap endonuclease 1 (FEN1) is crucial for DNA replication and repair, and its upregulation by DNA-damaging agents contributes to drug resistance.
  • The transcriptional regulation of FEN1 and its prognostic impact in human cancers remain unclear.

Purpose of the Study:

  • To identify transcription factors regulating FEN1 expression in human cancer.
  • To investigate the functional role of these factors in FEN1 expression and cancer cell response to chemotherapy.
  • To determine the correlation between FEN1 levels, treatment response, and patient survival in breast cancer.

Main Methods:

  • Utilized biochemical, molecular, and cellular approaches to identify and characterize FEN1 transcription factors/repressors.
  • Examined FEN1 promoter binding and gene expression changes in response to chemotherapeutic drugs (mitomycin C, Taxol).
  • Assessed FEN1 protein levels in human breast cancer specimens and correlated them with clinical outcomes.

Main Results:

  • FEN1 expression significantly increases upon treatment with chemotherapeutic drugs.
  • The transcription factor YY1 binds to the FEN1 promoter, suppressing its expression; YY1 dissociation leads to FEN1 overexpression.
  • Overexpression of YY1 sensitizes cancer cells to chemotherapy, and high FEN1 levels inversely correlate with drug/radiation resistance and patient survival.

Conclusions:

  • YY1 acts as a transcriptional repressor of FEN1, modulating its expression in response to DNA damage.
  • FEN1 is upregulated in human breast cancer.
  • Elevated FEN1 levels are associated with increased resistance to chemotherapy and radiation, and poorer patient survival.

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