Abstract
BackgroundDrug 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.MethodsTo 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.ResultsWe 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.ConclusionAltogether, 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1043-1) contains supplementary material, which is available to authorized users.
Highlights
Drug resistance is a major challenge in cancer therapeutics
We revealed that the elevated Flap endonuclease 1 (FEN1) level promotes the efficiency of Deoxyribonucleic acid (DNA) repair, which leads to drug resistance and poor prognostics
Identification and validation of transcription factor Yin Yang 1 (YY1) binding to FEN1 promoter We previously showed that the −458 to +278 region of the FEN1 gene promoter is essential to drive its expression [22]
Summary
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. FEN1 was previously shown to be upregulated in response to DNA damaging agents It is unclear about the transcription factors that regulate FEN1 expression in human cancer. The development of multidrug resistance (MDR) in cancer cells poses a major challenge to chemotherapy and greatly limits the anti-cancer efficacy of chemotherapeutic drugs [1,2]. Such resistance arises in cancer cells and cancer stem-like-cells because of the alteration in drug transport and metabolism that results in low level of anticancer efficacy, and because of the increased tolerance for DNA lesion and enhanced DNA replication and repair capacity [1,2,3,4,5]. Inhibition of DNA repair has successfully sensitized the cancer cells to cytotoxic killing by chemotherapeutic drugs [7]
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