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Nkx-2.5 Regulates MDR1 Expression via Its Upstream Promoter in Breast Cancer Cells

Jung-Suk Lim1, Gyu Yeon Jung1, Seung-Yoon Park1

  • 1Department of Biochemistry, School of Medicine, Dongguk University, Gyeongju, Korea.

Journal of Korean Medical Science
|April 4, 2019
PubMed
Abstract

Insights

The transcription factor Nkx-2.5 activates the MDR1 upstream promoter (USP), increasing multidrug resistance gene expression in breast cancer cells. This identifies Nkx-2.5 as a key regulator in cancer multidrug resistance.

Area of Science:

  • Molecular biology
  • Cancer research
  • Gene regulation

Background:

  • Multidrug resistance (MDR) in cancer is often mediated by increased MDR1 gene expression.
  • The MDR1 gene has two promoters: upstream and downstream.
  • The molecular mechanisms regulating the MDR1 upstream promoter (USP) remain largely unknown.

Purpose of the Study:

  • To investigate the role of Nkx-2.5 in the transactivation of the MDR1 USP.
  • To identify the specific binding site of Nkx-2.5 on the MDR1 USP.

Main Methods:

  • Dual-luciferase reporter gene assays were used to assess MDR1 USP activity.
  • Quantitative real-time PCR measured MDR1 mRNA levels.
  • Promoter enzyme immunoassays and chromatin immunoprecipitation assays confirmed Nkx-2.5 binding to the MDR1 USP.

Main Results:

  • Nkx-2.5 significantly enhanced MDR1 USP activity and increased MDR1 mRNA expression in MCF7 breast cancer cells.
  • The Nkx-2.5 binding site was localized to the region between -71 and +12 of the MDR1 USP.
  • Mutation of the Nkx-2.5 binding site (+4 to +10) reduced Nkx-2.5-mediated activation, and direct binding was confirmed.

Conclusions:

  • Nkx-2.5 acts as a positive regulator for MDR1 USP transactivation in MCF7 breast cancer cells.
  • These findings contribute to understanding the regulatory mechanisms underlying the multidrug-resistant cancer phenotype.
Keywords:
Breast CancerMDR1Nkx-2.5Transcriptional Regulation

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