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UHRF1 inhibits MDR1 gene transcription and sensitizes breast cancer cells to anticancer drugs

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Abstract

Overexpression of MDR1 in breast cancer remains a major cause for the failure of chemotherapy. In the present report, we find UHRF1 plays an important role in inhibiting MDR1 promoter activity by directly binding to the MDR1 promoter. Knockdown of UHRF1 activates MDR1 promoter activity and expression, attenuates the binding of UHRF1 and HDAC1 to the MDR1 promoter. Overexpression of UHRF1 in NCI/ADR-RES cells can induce deacetylation of histones H3 and H4 on the MDR1 promoter, which is facilitated by recruitment of HDAC1 to the MDR1 promoter. Loss of histone acetylation is accompanied by loss of binding of the key transcription factor, MyoD, CBP and p300, locking in marked suppression of MDR1, increasing sensitivity of MDR cancer cells to cytotoxic drugs that are transported by P-glycoprotein (P-gp). The inhibition of MDR1 expression by UHRF1 may provide potential ways to overcome multidrug resistance (MDR) in breast cancer treatment.

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Abbreviations

MDR:

Multidrug resistance

P-gp:

P-glycoprotein

HAT:

Histone acetyltransferase

HDAC1:

Histone deacetylase 1

PBS:

Phosphate-buffered saline

FBS:

Fetal bovine serum

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Acknowledgments

This study was supported by the grants from the Innovation Program of Shanghai Municipal Education Commission (No. 09ZZ04); the Natural Science Foundation of Shanghai (No. 09ZR1406900); and Shanghai Pujiang Program and Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry.

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Authors and Affiliations

  1. Department of Breast Surgery, Breast Cancer Institute, Cancer Hospital/Cancer Institute, Shanghai Medical College, Institute of Biomedical Science, Fudan University, Shanghai, 200032, People’s Republic of China

    Wei Jin, Si-guang Xu, Wen-jin Yin, Jun-jie Li & Zhi-ming Shao

  2. Department of Breast Surgery, Breast Cancer Institute, Cancer Hospital/Cancer Institute, Fudan University, 270 Dong’An Road, Shanghai, 200032, People’s Republic of China

    Wei Jin & Zhi-ming Shao

  3. School of Life Science, Liaoning Normal University, 850 Huanghe Road, Dalian, 116029, People’s Republic of China

    Yang Liu

  4. Department of Pharmacology, The Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey/Robert Wood Johnson Medical School, 195 Little Albany Street, New Brunswick, NJ, 08903, USA

    Jin-ming Yang

Authors
  1. Wei Jin
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  2. Yang Liu
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  3. Si-guang Xu
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  4. Wen-jin Yin
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  5. Jun-jie Li
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  6. Jin-ming Yang
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  7. Zhi-ming Shao
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Corresponding authors

Correspondence to Wei Jin or Zhi-ming Shao.

Additional information

Wei Jin, Yang Liu and Si-guang Xu contributed equally to the present study.

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Jin, W., Liu, Y., Xu, Sg. et al. UHRF1 inhibits MDR1 gene transcription and sensitizes breast cancer cells to anticancer drugs. Breast Cancer Res Treat 124, 39–48 (2010). https://doi.org/10.1007/s10549-009-0683-8

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  • DOI: https://doi.org/10.1007/s10549-009-0683-8

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