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

Wang, Jianwei; Zhou, Lina; Li, Zhi; Zhang, Ting; Liu, Wenpeng; Liu, Zheng; Yuan, Yate-Ching; Su, Feng; Lu, Xu; Wang, Yan; Zhou, Xiaotong; Xu, Hong; Hua, Yuejin; Wang, Yingjie; Zheng, Li; Teng, Yuee; Shen, Binghui

doi:10.1186/s12885-015-1043-1

Cited by 54 publications

(53 citation statements)

References 65 publications

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“…High expression of FEN1 appeared to associate in a statistically significant manner with highly malignant tumors ( p < 0.05) and tumors of advanced TNM stage ( p < 0.05). Moreover, consistent with this result and our previous report (Wang et al, 2015), Kaplan-Meier analyses revealed that breast cancer patients with high expression of FEN1 have poor prognoses (Fig. 1g).…”

Section: Resultssupporting

confidence: 92%

Targeting DNA Flap Endonuclease 1 to Impede Breast Cancer Progression

et al. 2016

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DNA flap endonuclease 1 (FEN1) plays critical roles in maintaining genome stability and integrity by participating in both DNA replication and repair. Suppression of FEN1 in cells leads to the retardation of DNA replication and accumulation of unrepaired DNA intermediates, resulting in DNA double strand breaks (DSBs) and apoptosis. Therefore, targeting FEN1 could serve as a potent strategy for cancer therapy. In this study, we demonstrated that FEN1 is overexpressed in breast cancers and is essential for rapid proliferation of cancer cells. We showed that manipulating FEN1 levels in cells alters the response of cancer cells to chemotherapeutic drugs. Furthermore, we identified a small molecular compound, SC13 that specifically inhibits FEN1 activity, thereby interfering with DNA replication and repair in vitro and in cells. SC13 suppresses cancer cell proliferation and induces chromosome instability and cytotoxicity in cells. Importantly, SC13 sensitizes cancer cells to DNA damage-inducing therapeutic modalities and impedes cancer progression in a mouse model. These findings could establish a paradigm for the treatment of breast cancer and other cancers as well.

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Section: Resultssupporting

confidence: 92%

Targeting DNA Flap Endonuclease 1 to Impede Breast Cancer Progression

et al. 2016

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“…FEN1 is overexpressed in many forms of cancer and has been reported as a potential biomarker and target in different types of cancer. Knockdown of FEN1 could inhibit of proliferation of cancer cells . Our data revealed that the growth of HeLa cells was delayed when FEN1 activity was inhibited, which confirmed the previous observation.…”

Section: Discussionsupporting

confidence: 91%

FEN1 inhibitor increases sensitivity of radiotherapy in cervical cancer cells

Wang

Chang

et al. 2019

Cancer Medicine

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BackgroundCervical cancer is one of the most common causes of cancer‐associated mortality among affected women in the world. At present, treatment with weekly cisplatin plus ionizing radiation (IR) therapy is the standard regimen for cervical cancer, especially for locally advanced cervical cancer. The purpose of this study is to determine whether FEN1 inhibitors could enhance the therapeutic effect of IR therapy.MethodsWestern blot was applied to determine the expression of FEN1‐ and apoptosis‐related proteins. Cell growth inhibition assay and colony formation assay were used to determine the effects of FEN1 inhibitor and IR exposure for Hela cells in vitro. CRISPR technology was used to knockdown FEN1 expression level of 293T cells, and tumor xenograft in nude mice was employed to determine the effects of FEN1 inhibitor and IR exposure on tumor growth in vivo.ResultsOur data revealed that FEN1 is overexpressed in HeLa cell and can be upregulated further by IR. We also demonstrated that FEN1 inhibitor enhances IR sensitivity of cervical cancer in vitro and in vivo.ConclusionFEN1 inhibitor SC13 could sensitize radiotherapy of cervical cancer cell.

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“…Fen1 is a highly versatile protein and performs various cellular functions, depending on its interaction with different proteins [81]. In breast cancer cells, Fen1 is significantly up-regulated upon treatment of chemotherapeutic drugs such as mitomycin C (MMC) and Taxol, which is regulated by transcription factor/repressor YY1 [97]. YY1 down-regulates Fen1 and sensitizes the breast cancer cells to these drugs.…”

Section: Role Of Fen1 In Dna Replication Recombination and Repairmentioning

confidence: 99%

“…From a clinical point of view, the repression of Fen1 level by the YY1 transcription factor has been shown to increase the sensitivity of breast cancer cells to MMC and Taxol [97]. Similarly, as we have shown that APC blocks Fen1 activity [47] and targeting Fen1(D181) with a small molecule increases the sensitivity of colon cancer cells to temozolomide (TMZ) [150], it can be hypothesized that APC mediated blockade of Fen1 activity may also increase the sensitization of breast cancer cells to DNA damaging agents.…”

Section: Polymorphic Variations In Apc and Fen1 Genes That May Affmentioning

confidence: 99%

Interaction between APC and Fen1 during breast carcinogenesis

et al. 2016

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Aberrant DNA base excision repair (BER) contributes to malignant transformation. However, inter-individual variations in DNA repair capacity plays a key role in modifying breast cancer risk. We review here emerging evidence that two proteins involved in BER – adenomatous polyposis coli (APC) and flap endonuclease 1 (Fen1) – promote the development of breast cancer through novel mechanisms. APC and Fen1 expression and interaction is increased in breast tumors versus normal cells, APC interacts with and blocks Fen1 activity in Pol-β-directed LP-BER, and abrogation of LP-BER is linked with cigarette smoke condensate-induced transformation of normal breast epithelial cells. Carcinogens increase expression of APC and Fen1 in spontaneously immortalized human breast epithelial cells, human colon cancer cells, and mouse embryonic fibroblasts. Since APC and Fen1 are tumor suppressors, an increase in their levels could protect against carcinogenesis; however, this does not seem to be the case. Elevated Fen1 levels in breast and lung cancer cells may reflect the enhanced proliferation of cancer cells or increased DNA damage in cancer cells compared to normal cells. Inactivation of the tumor suppressor functions of APC and Fen1 is due to their interaction, which may act as a susceptibility factor for breast cancer. The increased interaction of APC and Fen1 may occur due to polypmorphic and/or mutational variation in these genes. Screening of APC and Fen1 polymorphic and/or mutational variations and APC/Fen1 interaction may permit assessment of individual DNA repair capability and the risk for breast cancer development. Such individuals might lower their breast cancer risk by reducing exposure to carcinogens. Stratifying individuals according to susceptibility would greatly assist epidemiologic studies of the impact of suspected environmental carcinogens. Additionally, a mechanistic understanding of the interaction of APC and Fen1 may provide the basis for developing new and effective targeted chemopreventive and chemotherapeutic agents.

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

Cited by 54 publications

References 65 publications

Targeting DNA Flap Endonuclease 1 to Impede Breast Cancer Progression

Targeting DNA Flap Endonuclease 1 to Impede Breast Cancer Progression

FEN1 inhibitor increases sensitivity of radiotherapy in cervical cancer cells

Interaction between APC and Fen1 during breast carcinogenesis

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