FEN1 endonuclease as a therapeutic target for human cancers with defects in homologous recombination

Guo, Elaine; Ishii, Yuki; Mueller, James L.; Srivatsan, Anjana; Gahman, Timothy C.; Putnam, Christopher D.; Wang, Jean Y. J.; Kolodner, Richard D.

doi:10.1073/pnas.2009237117

Cited by 71 publications

(62 citation statements)

References 73 publications

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“…Upstream regulatory mechanisms of FEN1 in lung cancer was investigated in this study (33). The latest study identi ed that small molecule inhibitors of FEN1 can signi cantly suppress the progression of homologous recombination (HR) de cient tumors, suggesting that FEN1 is a therapeutic target for HR de cient tumors (34). Correlations between FEN1 and drug resistance were reported.…”

Section: Discussionmentioning

confidence: 97%

A Bibliometric Analysis of Researches on Flap Endonuclease 1 From 2005 to 2019

Wei

Shen

Wang

et al. 2021

Preprint

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Background: Flap endonuclease 1 (FEN1) is a structure-specific nuclease that plays a role in a variety of DNA metabolism processes. FEN1 is important for maintaining genomic stability and regulating cell growth and development. It is associated with the occurrence and development of several diseases, especially cancers. There is a lack of systematic bibliometric analyses focusing on research trends and knowledge structures related to FEN1.Purpose: To analyze hotspots, the current state and research frontiers performed for FEN1 over the past 15 years. Methods: Publications were retrieved from the Web of Science Core Collection (WoSCC) database, analyzing publication dates ranging from 2005 to 2019. VOSviewer1.6.15 and Citespace5.7 R1 were used to perform a bibliometric analysis in terms of countries, institutions, authors, journals and research areas related to FEN1. A total of 421 publications were included in this analysis. Results: Our findings indicated that FEN1 has received more attention and interest from researchers in the past 15 years. Institutes in the United States, specifically the Beckman Research Institute of City of Hope published the most research related to FEN1. SHEN BH，ZHENG L and BAMBARA RA were the most active researchers investigating this endonuclease and most of this research was published in the Journal of Biological Chemistry. The main scientific areas of FEN1 were related to biochemistry, molecular biology，cell biology，genetics and oncology. Research hotspots included biological activities, DNA metabolism mechanisms, protein-protein interactions and gene mutations. Research frontiers included oxidative stress, phosphorylation and tumor progression and treatment. Conclusion: This bibliometric study may aid researchers in the understanding of the knowledge base and research frontiers associated with FEN1. In addition, emerging hotspots for research can be used as the subjects of future studies.

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Section: Discussionmentioning

confidence: 97%

A Bibliometric Analysis of Researches on Flap Endonuclease 1 From 2005 to 2019

Wei

Shen

Wang

et al. 2021

Preprint

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“…FEN1 overexpression increases breast cancer progression and its transcription is also activated following anti-cancer treatments. Therefore its inhibition is a potential approach to overcome resistance mechanisms [49][50][51][52][53]. NEIL3 is also overexpressed in breast invasive carcinoma and its upregulation positively correlates with the decrease in the survival of triple negative breast cancer (TNBC) patients [54][55][56].…”

Section: Plos Onementioning

confidence: 99%

The overexpression of DNA repair genes in invasive ductal and lobular breast carcinomas: Insights on individual variations and precision medicine

et al. 2021

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In the era of precision medicine, analyzing the transcriptomic profile of patients is essential to tailor the appropriate therapy. In this study, we explored transcriptional differences between two invasive breast cancer subtypes; infiltrating ductal carcinoma (IDC) and lobular carcinoma (LC) using RNA-Seq data deposited in the TCGA-BRCA project. We revealed 3854 differentially expressed genes between normal ductal tissues and IDC. In addition, IDC to LC comparison resulted in 663 differentially expressed genes. We then focused on DNA repair genes because of their known effects on patients’ response to therapy and resistance. We here report that 36 DNA repair genes are overexpressed in a significant number of both IDC and LC patients’ samples. Despite the upregulation in a significant number of samples, we observed a noticeable variation in the expression levels of the repair genes across patients of the same cancer subtype. The same trend is valid for the expression of miRNAs, where remarkable variations between patients’ samples of the same cancer subtype are also observed. These individual variations could lie behind the differential response of patients to treatment. The future of cancer diagnostics and therapy will inevitably depend on high-throughput genomic and transcriptomic data analysis. However, we propose that performing analysis on individual patients rather than a big set of patients’ samples will be necessary to ensure that the best treatment is determined, and therapy resistance is reduced.

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“…participates in numerous DNA processing pathways 22 , recent study uncovered that FEN1 inhibition sensitized cancer cells to drugs 23 . Furthermore, GEPIA analyze showed that IGF-1R expression was positively correlated with FEN1 (p < 0.001, r = 0.45, Fig.…”

Section: Igf-1r/mir-610/fen1 Expression In Os Tissuesmentioning

confidence: 99%

Metformin Sensitizes Osteosarcoma Cells to Chemotherapy Through IGF-1R/miR-610/FEN1 Pathway

Dong¹,

Zhu³

et al. 2021

Preprint

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Background: Due to constitutive or acquired non-sensitive to cytotoxic agents, the prognosis of osteosarcoma remains unfavorable. It’s has been proved that metformin could enhance the chemosensitivity of cancer cells to anticancer drugs. A novel finding states that IGF-1R involves in cancer chemoresistance, However, whether IGF-1R play a role in metformin-induced osteosarcoma chemosensitivity is incompletely understood. Hence, the current study aimed to elucidate the role of metformin in OS cell chemosensitivity modulation to identify the underlying mechanism of metformin regulating the IGF-1R/miR-610/FEN1 signaling.Methods: Immunohistochemistry and qRT-PCR were used to evaluate the expression pattern of IGF-1R, miR-610 and FEN1 in osteosarcoma and paired normal tissues. Western blot and qRT-PCR were performed to determine changes in expression of key molecules in the IGF-1R/miR-610/FEN1 signaling pathway after various treatments. The direct modulation between miR-610 and FEN1 was monitored by luciferase reporter assay. Osteosarcoma cell sensitivity to chemotherapy was detected by MTS assay. In vivo experiments were conducted to further verify the role of the metformin in the chemosensitivity modulation of OS cells to ADM.Results: We found that IGF-1R, miR-610 and FEN1 were abberently expressed in osteosarcoma, and participated in apoptosis modulation (p < 0.05). We found that this effect was abated by metformin treatment. Luciferase reporter assays confirmed that FEN1 is a direct target of miR-610. Moreover, we observed that metformin treatment decreased IGF-1R and FEN1, but elevated miR-610 expression. Metformin sensitized OS cells to cytotoxic agents, while overexpression of FEN1 compromised the sensitizing effects of metformin partly. Furthermore, metformin was observed to enforce the ADM treatment effect in nude mice xenograft models.Conclusions: Overall, metformin enhanced the sensitivity of OS cells to cytotoxic agents via the IGF-1R/miR-610/FEN1 signaling axis, highlighting the capacity of metformin as an adjunct to the chemotherapy of OS.

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FEN1 endonuclease as a therapeutic target for human cancers with defects in homologous recombination

Cited by 71 publications

References 73 publications

A Bibliometric Analysis of Researches on Flap Endonuclease 1 From 2005 to 2019

A Bibliometric Analysis of Researches on Flap Endonuclease 1 From 2005 to 2019

The overexpression of DNA repair genes in invasive ductal and lobular breast carcinomas: Insights on individual variations and precision medicine

Metformin Sensitizes Osteosarcoma Cells to Chemotherapy Through IGF-1R/miR-610/FEN1 Pathway

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