The online version of this article (doi:10.1186/s12885-015-1043-1) contains supplementary material, which is available to authorized users.
The authors declare that they have no competing interests.
BS, LZ, YH, YW, and YT conceived and designed the experiments. JW, LNZ, TZ, WL, HX performed biochemical, molecular, and cellular studies on YY1 function to regulate FEN1 expression and the impact on drug resistance. ZLi, ZLiu, YCY, FS, LX, YW, XZ analyze FEN1 expression in human breast cancer and conduct data collecting, mining, and analysis on patient prognostic outcome. BS, LZ, YH, YW, and YT interpret data and write manuscript. All authors read and approved the final manuscript.
The authors wish it to be known that, in their opinion, the first two authors, Jianwei Wang and Lina Zhou should be regarded as joint first authors.
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.
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.
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.
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.
Additional file 1: Table S1. Correlation between FEN1 or YY1 expression and clinicopathologic variables. Table S2. Univariate and multivariate analyses of OS according to clinicopathologic variables. Table S3. Univariate and multivariate analyses of OS according to biomarkers adjusted by selected clinicopathologic variables. Table S4. Univariate and multivariate analyses of DFS according to clinicopathologic variables. Table S5. Univariate and multivariate analyses of DFS according to biomarkers adjusted by selected clinicopathologic variables. Table S6. All the DNA oligonucleotides used in the current study.12885_2015_1043_MOESM1_ESM.pdf
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- YY1 suppresses FEN1 over-expression and drug resistance in breast cancer
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