HSP90 inhibition downregulates DNA replication and repair genes via E2F1 repression

Liu, Hanqing; Lu, Ziwen; Shi, Xiaofeng; Liu, Lanlan; Zhang, Peishan; Golemis, Erica A.; Tu, Zhigang

doi:10.1016/j.jbc.2021.100996

Cited by 14 publications

(18 citation statements)

References 71 publications

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“…It is widely acknowledged that DNA replication ensures that cellular genetic information is accurately copied and correctly transmitted to offspring cells [ 32 , 40 , 41 ]. However, DNA replication is prone to interference and damage under various pressures in the body, leading to stagnant DNA replication, affecting genome stability, and even inducing apoptosis [ 42 ], necrosis [ 43 ], and carcinogenesis [ 44 ]. Pathway enrichment analysis suggested that MAD2L1 affected the pathogenesis of proliferation and apoptosis in hepatocellular carcinoma via the above pathways.…”

Section: Discussionmentioning

confidence: 99%

Identification of MAD2L1 as a Potential Biomarker in Hepatocellular Carcinoma via Comprehensive Bioinformatics Analysis

Chen

Yang

Zhang

et al. 2022

BioMed Research International

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Background. Hepatocellular carcinoma (HCC) is widely acknowledged as a malignant tumor with rapid progression, high recurrence rate, and poor prognosis. At present, there is a paucity of reliable biomarkers at the clinical level to guide the management of HCC and improve patient outcomes. Our research is aimed at assessing the prognostic value of MAD2L1 in HCC. Methods. Four datasets, GSE121248, GSE101685, GSE85598, and GSE62232, were selected from the GEO database to analyze differentially expressed genes (DEGs) between HCC and normal liver tissues. After functional analysis, we constructed a protein-protein interaction network (PPI) for DEGs and identified core genes in this network with high connectivity with other genes. We assessed the relationship between core genes and the pathogenesis and prognosis of HCC. Finally, we explored the gene regulatory signaling mechanisms involved in HCC pathogenesis. Results. 145 DEGs were screened from the intersection of the four GEO datasets. MAD2L1 was associated with most genes according to the PPI network and was selected as a candidate gene for further study. Survival analysis suggested that high MAD2L1 expression in HCC correlated with a worse prognosis. In addition, real-time quantitative PCR (RT-qPCR), western blot (WB), and immunohistochemistry (IHC) findings suggested that the expression of MAD2L1 was abnormally increased in HCC tissues and cells compared to paraneoplastic tissues and normal hepatocytes. Conclusion. We found that high MAD2L1 expression in HCC was significantly associated with overall patient survival and clinical features. We also explored the potential biological properties of this gene.

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Section: Discussionmentioning

confidence: 99%

Identification of MAD2L1 as a Potential Biomarker in Hepatocellular Carcinoma via Comprehensive Bioinformatics Analysis

Chen

Yang

Zhang

et al. 2022

BioMed Research International

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“…E2F1 has been attributed to numerous cancer hallmarks in prostate cancer, including cell cycle, proliferation and apoptosis [ 45 ], and its expression is so closely aligned with disease stage that it has been proposed as a potential biomarker [ 46 , 47 ]. Notably, AR, MYC and E2F1/2 are all established Hsp90 client proteins, and targeting Hsp90 inhibits expression of AR in prostate cancer (reviewed in [ 41 ]), and MYC [ 48 , 49 , 50 , 51 ] and E2F1 [ 52 , 53 ] in other cancers. Our ability to identify known pathways associated with Hsp90 and prostate cancer through omics analysis of PDE tissues highlights the capacity for omics identification of novel targets and biomarkers in the face of prostate tumor heterogeneity.…”

Section: Discussionmentioning

confidence: 99%

Harnessing the Heterogeneity of Prostate Cancer for Target Discovery Using Patient-Derived Explants

Centenera

Vincent

Moldovan

et al. 2022

Cancers

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Prostate cancer is a complex and heterogeneous disease, but a small number of cell lines have dominated basic prostate cancer research, representing a major obstacle in the field of drug and biomarker discovery. A growing lack of confidence in cell lines has seen a shift toward more sophisticated pre-clinical cancer models that incorporate patient-derived tumors as xenografts or explants, to more accurately reflect clinical disease. Not only do these models retain critical features of the original tumor, and account for the molecular diversity and cellular heterogeneity of prostate cancer, but they provide a unique opportunity to conduct research in matched tumor samples. The challenge that accompanies these complex tissue models is increased complexity of analysis. With over 10 years of experience working with patient-derived explants (PDEs) of prostate cancer, this study provides guidance on the PDE method, its limitations, and considerations for addressing the heterogeneity of prostate cancer PDEs that are based on statistical modeling. Using inhibitors of the molecular chaperone heat shock protein 90 (Hsp90) as an example of a drug that induces robust proliferative response, we demonstrate how multi-omics analysis in prostate cancer PDEs is both feasible and essential for identification of key biological pathways, with significant potential for novel drug target and biomarker discovery.

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“…By focusing on the differences between the heat stressed groups to evaluate the effect of HSP70 supplementation, we observed differences in the expression of three genes ( HSF1, HSP90AA1 and ATP1A1 ) that had a strong tendency towards significant downregulated in the H41 ( Figure 1 ). HSP90AA1 belongs to the family of HSP90 and encodes for a molecular chaperon, which participates in the proper folding of misfolded proteins using an ATPase activity; however, the protein is involved also in other functions, such as cell signalling, transcription and DNA replications and repair [ 74 , 75 ], yet they require excessive amounts of cellular energy to mitigate the negative effects of heat stress in cellular level. The roles of HSF1 and ATP1A1 are thoroughly discussed in the previous sections of the discussion.…”

Section: Discussionmentioning

confidence: 99%

The Effects of Heat Shock Protein 70 Addition in the Culture Medium on the Development and Quality of In Vitro Produced Heat Shocked Bovine Embryos

Stamperna

Giannoulis

Dovolou

et al. 2021

Animals

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The aims of the present study were to examine the effects of HSP70 addition in the in vitro culture medium of day 3 embryos on their developmental competence and quality. Bovine oocytes (n = 1442) were in vitro matured, inseminated and cultured for the first two days according to standardized methods. The presumptive zygotes were randomly allocated in three experimental groups: Control, C (embryos cultured at 39 °C throughout the culture period), group C41 (temperature was raised to 41 °C from the 48th to 72nd h post insemination (p.i.) and then it returned at 39 °C for the remaining culture period), and group H41 (the temperature modification was the same as in C41 and during heat exposure, HSP70 was added in the culture medium). Cleavage and embryo yield were assessed 48 h p.i. and on days 7, 8, 9, respectively and gene expression in day 7 blastocysts was assessed by RT-PCR. Blastocyst yield was the highest in group C39; and higher in group H41 compared to group C41. From the gene expression analyses, altered expression of 11 genes was detected among groups. The analysis of the orchestrated patterns of gene expression differed between groups. The results of this study confirm the devastating effects of heat stress on embryo development and provide evidence that HSP70 addition at the critical stages can partly counterbalance, without neutralizing, the negative effects of the heat insult on embryos, acting mainly through mechanisms related to energy deployment.

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HSP90 inhibition downregulates DNA replication and repair genes via E2F1 repression

Cited by 14 publications

References 71 publications

Identification of MAD2L1 as a Potential Biomarker in Hepatocellular Carcinoma via Comprehensive Bioinformatics Analysis

Identification of MAD2L1 as a Potential Biomarker in Hepatocellular Carcinoma via Comprehensive Bioinformatics Analysis

Harnessing the Heterogeneity of Prostate Cancer for Target Discovery Using Patient-Derived Explants

The Effects of Heat Shock Protein 70 Addition in the Culture Medium on the Development and Quality of In Vitro Produced Heat Shocked Bovine Embryos

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