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BMC Cancer
Published in: BMC Cancer 1/2015

Open Access 01-12-2015 | Research article

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

Authors: Jianwei Wang, Lina Zhou, Zhi Li, Ting Zhang, Wenpeng Liu, Zheng Liu, Yate-Ching Yuan, Fan Su, Lu Xu, Yan Wang, Xiaotong Zhou, Hong Xu, Yuejin Hua, Ying-Jie Wang, Li Zheng, Yue-E Teng, Binghui Shen

Published in: BMC Cancer | Issue 1/2015

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Abstract

Background

Drug resistance is a major challenge in cancer therapeutics. Abundant evidence indicates that DNA repair systems are enhanced after repetitive chemotherapeutic treatments, rendering cancers cells drug-resistant. Flap endonuclease 1 (FEN1) plays critical roles in DNA replication and repair and in counteracting replication stress, which is a key mechanism for many chemotherapeutic drugs to kill cancer cells. FEN1 was previously shown to be upregulated in response to DNA damaging agents. However, it is unclear about the transcription factors that regulate FEN1 expression in human cancer. More importantly, it is unknown whether up-regulation of FEN1 has an adverse impact on the prognosis of chemotherapeutic treatments of human cancers.

Methods

To reveal regulation mechanism of FEN1 expression, we search and identify FEN1 transcription factors or repressors and investigate their function on FEN1 expression by using a combination of biochemical, molecular, and cellular approaches. Furthermore, to gain insights into the impact of FEN1 levels on the response of human cancer to therapeutic treatments, we determine FEN1 levels in human breast cancer specimens and correlate them to the response to treatments and the survivorship of corresponding breast cancer patients.

Results

We observe that FEN1 is significantly up-regulated upon treatment of chemotherapeutic drugs such as mitomycin C (MMC) and Taxol in breast cancer cells. We identify that the transcription factor/repressor YY1 binds to the FEN1 promoter and suppresses the expression of FEN1 gene. In response to the drug treatments, YY1 is dissociated from the FEN1 promoter region leading over-expression of FEN1. Overexpression of YY1 in the cells results in down-regulation of FEN1 and sensitization of the cancer cells to MMC or taxol. Furthermore, we observe that the level of FEN1 is inversely correlated with cancer drug and radiation resistance and with survivorship in breast cancer patients.

Conclusion

Altogether, our current data indicate that YY1 is a transcription repressor of FEN1 regulating FEN1 levels in response to DNA damaging agents. FEN1 is up-regulated in human breast cancer and its levels inversely correlated with cancer drug and radiation resistance and with survivorship in breast cancer patients.
Appendix
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Metadata
Title
YY1 suppresses FEN1 over-expression and drug resistance in breast cancer
Authors
Jianwei Wang
Lina Zhou
Zhi Li
Ting Zhang
Wenpeng Liu
Zheng Liu
Yate-Ching Yuan
Fan Su
Lu Xu
Yan Wang
Xiaotong Zhou
Hong Xu
Yuejin Hua
Ying-Jie Wang
Li Zheng
Yue-E Teng
Binghui Shen
Publication date
01-12-2015
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2015
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-015-1043-1

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