IER5 as a promising predictive marker promotes irradiation-induced apoptosis in cervical cancer tissues from patients undergoing chemoradiotherapy

Yang, Liu; Tian, Mei; Zhao, Hui; He, Yue; Li, Fengshuang; Li, Xiunan; Yu, Xinmin; Ding, Kun; Zhou, Ping; Wu, Yumei

doi:10.18632/oncotarget.16857

Cited by 8 publications

(10 citation statements)

References 24 publications

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“…Moreover, the expression level of PAF1 in both the Siha and Hela cells was decreased after radiation Studies in recent years have suggested that PAF1 is a pivotal transcription factor for certain "induced" genes [32]. Since the results from our earlier studies demonstrated that the expression of IER5 could be induced in radiation-exposed CC cells [12], in this study, we correlated PAF1 with IER5 in both CC tissue and different cell lines. First, the localization analysis of IER5 in cells from CC tissue revealed anti-correlated expression with PAF1.…”

Section: Discussionmentioning

confidence: 85%

“…Efforts have been made to identify genes responsible for controlling radiosensitivity in CC cells, which involve DNA damage repair [3,4], cell cycle monitoring [5,6], apoptosis [7,8], signal transduction [9,10], and the tumor microenvironment [11]. Results from our previous study showed that the expression of immediate-early response 5 (IER5) was upregulated in CC tissues after treatment with radiotherapy [12]. IER5, as a member of the early-response protein family, can be stimulated by sleep deprivation, hormones, radiation, drugs, etc.…”

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confidence: 99%

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Novel role of PAF1 in attenuating radiosensitivity in cervical cancer by inhibiting IER5 transcription

Zheng

Liu

et al. 2020

Radiat Oncol

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Background: Radiosensitivity is limited in cervical cancer (CC) patients due to acquired radiation resistance. In our previous studies, we found that immediate-early response 5 (IER5) is upregulated in CC cells upon radiation exposure and decreases cell survival by promoting apoptosis. The details on the transcriptional regulation of radiation-induced IER5 expression are unknown. Studies in recent years have suggested that Pol II-associated factor 1 (PAF1) is a pivotal transcription factor for certain genes "induced" during tumor progression. In this study, we investigated the role of PAF1 in regulating IER5 expression during CC radiotherapy. Methods: PAF1 expression in CC cells was measured by western blotting, immunohistochemistry, and qRT-PCR, and the localization of PAF1 and IER5 was determined by immunofluorescence. The effect of PAF1 and IER5 knockdown by siRNA in Siha and Hela cells was studied by western blotting, qRT-PCR, CCK-8 assay, and flow cytometry. The physical interaction of PAF1 with the IER5 promoter and enhancers was confirmed using chromatin immunoprecipitation and qPCR with or without enhancers knockout by CRISPR/Cas9. Results: We confirmed that PAF1 was highly expressed in CC cells and that relatively low expression of IER5 was observed in cells with highly expressed PAF1 in the nucleus. PAF1 knockdown in Siha and Hela cells was associated with increased expression of IER5, reduced cell viability and higher apoptosis rate in response to radiation exposure, while simultaneous PAF1 and IER5 knockdown had little effect on the proportion of apoptotic cells. We also found that PAF1 hindered the transcription of IER5 by promoting Pol II pausing at the promoter-proximal region, which was primarily due to the binding of PAF1 at the enhancers. Conclusions: PAF1 reduces CC radiosensitivity by inhibiting IER5 transcription, at least in part by regulating its enhancers. PAF1 might be a potential therapeutic target for overcoming radiation resistance in CC patients.

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Section: Discussionmentioning

confidence: 85%

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confidence: 99%

Novel role of PAF1 in attenuating radiosensitivity in cervical cancer by inhibiting IER5 transcription

Zheng

Liu

et al. 2020

Radiat Oncol

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“…The results of the present study indicated one CpG island and several potential methylation sites. Liu et al (10) and Shi et al (11) demonstrated that radiation could upregulate the expression levels of IER5 . Therefore, we proposed that the methylation levels of the wild type IER5 gene may be low, but could notably increase following radiation exposure, inducing its expression (24,25).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, Li et al (7), Kawabata et al (8) and Nakamura et al (9), also observed the cell cycle regulation by IER5 during the progression of different diseases. Our research group has demonstrated that radiation can induce upregulation of IER5 in tumor cells (10,11) and this process can modulate the transcription of cell division cycle ( CDC ) 25B by competitively binding to the CDC25B promoter (12). Additionally, we reported that decreased IER5 expression could increase the population of cancer cells in the G 2 /M phase of the cell cycle (13,14), and that binding of a novel transcription factor and GC binding factor (GCF) to the IER5 promoter could act as a negative regulator of IER5 transcriptional activity (15).…”

Section: Introductionmentioning

confidence: 99%

Prediction of IER5 structure and function using a bioinformatics approach

et al. 2019

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Immediate-early response gene 5 (IER5) is a gene involved in the regulation of the cell cycle, and its structure and function have been investigated by bioinformatics analyses. The present study determined the sites of promoter methylation and gene ontology (GO) annotations associated with IER5. In addition, we conducted a prediction analysis to determine the physical and chemical properties, hydrophobicity/hydrophilicity, posttranslational modification, subcellular localization, transmembrane structure, signal peptide and secondary and tertiary structures of IER5. One CpG island and several methylated sites were identified close to the promoter of IER5 . The GO analysis suggested that IER5 could bind ions and proteins that were mainly associated with metabolic processes. IER5 comprised 327 amino acids and was reported to be an unstable hydrophilic protein with an isoelectric point of 4.91. A total of 18 O-glycosylation sites and 22 phosphorylation sites were identified within this protein. The subcellular localization of IER5 was mainly in the nucleus, and its main secondary structural element was the α-helix. Bioinformatic analyses of the features of IER5 may improve understanding of its structure and function; however, experimental verification is required.

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“…A variety of genes are involved in the development of radioresistance in CC cells, such as thyroid hormone receptor interactor 4, hypoxia inducible factor‐1α and so on . Conversely, immediate‐early gene 5 can enhance the radiosensitivity of tumor cells and induce apoptosis of CC cells . Coactivator‐associated arginine methyltransferase 1 (CARM1) is a protein with arginine‐specific histone methyltransferase activity and is a coactivator of many nuclear receptors and transcription factors .…”

Section: Introductionmentioning

confidence: 99%

miR‐16‐5p modulates the radiosensitivity of cervical cancer cells via regulating coactivator‐associated arginine methyltransferase 1

Zhang

Wang

et al. 2019

Pathology International

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This study was to investigate the expression of coactivator‐associated arginine methyltransferase 1 (CARM1) and miR‐16‐5p in cervical cancer (CC), and explore their roles in radioresistance. Western blot and immunohistochemistry were used to detect the expression of CARM1 in tissues and cells. Reverse transcription‐polymerase chain reaction (RT‐PCR) was used to detect the expression of miR‐16‐5p. CC cells received different doses of X‐ray exposure, and then cell counting kit‐8 method and colony formation assay were used to detect cell proliferation. Apoptosis was detected by flow cytometry. Then we used Targetscan database to predict that CARM1 is a potential target of miR‐16‐5p, and further verified the targeting relationship between them by western blot, RT‐PCR and dual luciferase reporter experiments. We demonstrated that CARM1 were highly expressed in CC tissues and radio‐resistant CC cells, while miR‐16‐5p expression was low. Under irradiation, up‐regulation of CARM1 can induce radiotherapy resistance of CC cells, while overexpression of miR‐16‐5p or CARM1 knockdown could inhibit the survival of CC cell and induced apoptosis. CARM1 was verified as a target for miR‐16‐5p. Besides, up‐regulation of CARM1 reversed the increase in radiosensitivity induced by miR‐16‐5p. Collectively, we concluded that miR‐16‐5p promoted the radiosensitivity of CC cells by targeting CARM1.

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IER5 as a promising predictive marker promotes irradiation-induced apoptosis in cervical cancer tissues from patients undergoing chemoradiotherapy

Cited by 8 publications

References 24 publications

Novel role of PAF1 in attenuating radiosensitivity in cervical cancer by inhibiting IER5 transcription

Novel role of PAF1 in attenuating radiosensitivity in cervical cancer by inhibiting IER5 transcription

Prediction of IER5 structure and function using a bioinformatics approach

miR‐16‐5p modulates the radiosensitivity of cervical cancer cells via regulating coactivator‐associated arginine methyltransferase 1

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