Regulation of RAD51 at the Transcriptional and Functional Levels: What Prospects for Cancer Therapy?

Orhan, Esin; Velázquez, Carolina; Tabet, Imene; Sardet, Claude; Theillet, Charles

doi:10.3390/cancers13122930

Cited by 31 publications

(18 citation statements)

References 147 publications

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“…Finally, a plethora of other proteins fill in the missing sections of DNA and restore two matching copies [3]. RAD51 was expressed at high levels in multiple types of cancers and shown to be elevated in several types of malignancies compared with corresponding normal tissues [35]. The reports abovementioned provide the evidence that RAD51 has the potential to be a biomarker…”

Section: Discussionmentioning

confidence: 94%

A Pan-Cancer Analysis of the Oncogenic Roles of RAD51 in Human Tumors

Han

Liu

et al. 2022

Advanced Gut & Microbiome Research

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Objective. RAD51 homolog 1 (RAD51) plays significant roles in DNA damage repair and apoptosis. These pathways are tightly associated with tumor initiation and progression. To unravel the roles of RAD51 in oncogenesis and progression of different cancers, herein, a comprehensive analysis of the RAD51 was carried out using multiomics datasets of 33 cancers. Methods. Raw data were obtained from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases. We analyzed the correlation between RAD51 expression and drug response using datasets from CellMiner. Next, clinical characteristics and prognostic values of RAD51 were conducted based on TCGA data. The correlation between RAD51 expression and tumor immune infiltration was explored. This was followed by gene set enrichment analysis by Rsoftware. In addition, pan-cancer analysis was conducted to investigate genetic and epigenetic alterations, respectively. Results. RAD51 was upregulated in most tumors, and this was associated with poor overall survival (OS), progression-free survival (PFS), and disease-specific survival (DSS). The expression level of RAD51 is significantly associated with the IC50 of multiple antitumor drugs and the proportion of stromal and immune components in tumor microenvironment (TME). Moreover, RAD51 expression showed a positive relationship with multiple key immune checkpoint and immunosuppressive genes, including death-ligand 1 (PD-L1), cytotoxic T-lymphocyte associated protein 4 (CTLA-4), CD28, and several TNF-related immune genes. Gene set enrichment analysis uncovered that RAD51 correlated with cell cycle, cell division, and immune system pathways in diverse cancers. Our results revealed a strong link between RAD51 expression and microsatellite instability (MSI) or tumor mutation burden (TMB). Conclusions. Our pan-cancer analysis provides a comprehensive overview of the roles of RAD51 in multiple human cancers and infers that RAD51 has the potential as a biomarker for progression and immune infiltration of different tumor types.

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Section: Discussionmentioning

confidence: 94%

A Pan-Cancer Analysis of the Oncogenic Roles of RAD51 in Human Tumors

Han

Liu

et al. 2022

Advanced Gut & Microbiome Research

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“…BRCAde cient ovarian and breast cancers with HRD show sensitivity to PARP inhibitors and DNA-damaging drugs such as platinum, because these drugs arrest a large number of replication forks and lead to synthetic lethality [70]. Since these processes can be circumvented by RAD51, which plays a central role in the repair and restart of replication forks [71,72], the high expression of RAD51 is thought to lead to resistance to these drugs [73]. RAD51 histological expression as identi ed by uorescent immunostaining was found to re ect homologous recombination repair function and was claimed as a predictive marker of pCR after NAC in TNBC [74].…”

Section: Discussionmentioning

confidence: 99%

High RAD51 gene expression is associated with aggressive biology and with poor survival in breast cancer

Patel

Tokumaru

et al. 2022

Breast Cancer Res Treat

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Purpose: Although DNA repair mechanism is a key to prevent carcinogenesis, its activation in established cancer cells may support their proliferation and aggravate cancer progression. RAD51 cooperates with BRCA2 and is essential in the homologous recombination of DNA repair. To this end, we hypothesized that RAD51 gene expression is associated with cancer cell proliferation and poor prognosis of breast cancer (BC) patients.Methods: A total of 8515 primary BC patients with transcriptome and clinical data from 17 independent cohorts were analyzed. Median was used to divide each cohort into high and low RAD51 expression groups.Results: High RAD51 expression enriched DNA repair gene set and was correlated with DNA repair-related genes. Nottingham histological grade, Ki67 expression and cell proliferation-related gene sets (E2F Targets, G2M Checkpoint and Myc Targets) were all signi cantly associated with the high RAD51 BC.RAD51 expression was positively correlated with Homologous Recombination De ciency, as well as both mutation burden and neoantigen that accompanied with higher in ltration of immune cells. Primary BC with lymph node metastases were associated with high expression of RAD51 in 2 cohorts. There was no strong correlation between RAD51 expression and drug sensitivity in cell lines, and RAD51 expression was lower after the neoadjuvant chemotherapy compared to before the treatment. High RAD51 BC was associated with poor prognosis consistently in 3 independent cohorts. Conclusion: RAD51 gene expression is associated with aggressive cancer biology, cancer cell proliferation, and poor survival in breast cancer.

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“…RAD51 is overexpressed in various cancers, including malignant gliomas and cancers of the liver, ovary, breast, lung, pancreas, colon, and rectum [ 51 ]. In addition, its expression shows a significant negative correlation with disease prognosis [ 52 ].…”

Section: Discussionmentioning

confidence: 99%

Hydroxygenkwanin Increases the Sensitivity of Liver Cancer Cells to Chemotherapy by Inhibiting DNA Damage Response in Mouse Xenograft Models

Chen

Cheng

Shieh

et al. 2021

IJMS

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Molecules involved in DNA damage response (DDR) are often overexpressed in cancer cells, resulting in poor responses to chemotherapy and radiotherapy. Although treatment efficacy can be improved with the concomitant use of DNA repair inhibitors, the accompanying side effects can compromise the quality of life of patients. Therefore, in this study, we identified a natural compound that could inhibit DDR, using the single-strand annealing yeast-cell analysis system, and explored its mechanisms of action and potential as a chemotherapy adjuvant in hepatocellular carcinoma (HCC) cell lines using comet assay, flow cytometry, Western blotting, immunofluorescence staining, and functional analyses. We developed a mouse model to verify the in vitro findings. We found that hydroxygenkwanin (HGK) inhibited the expression of RAD51 and progression of homologous recombination, thereby suppressing the ability of the HCC cell lines to repair DNA damage and enhancing their sensitivity to doxorubicin. HGK inhibited the phosphorylation of DNA damage checkpoint proteins, leading to apoptosis in the HCC cell lines. In the mouse xenograft model, HGK enhanced the sensitivity of liver cancer cells to doxorubicin without any physiological toxicity. Thus, HGK can inhibit DDR in liver cancer cells and mouse models, making it suitable for use as a chemotherapy adjuvant.

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Regulation of RAD51 at the Transcriptional and Functional Levels: What Prospects for Cancer Therapy?

Cited by 31 publications

References 147 publications

A Pan-Cancer Analysis of the Oncogenic Roles of RAD51 in Human Tumors

A Pan-Cancer Analysis of the Oncogenic Roles of RAD51 in Human Tumors

High RAD51 gene expression is associated with aggressive biology and with poor survival in breast cancer

Hydroxygenkwanin Increases the Sensitivity of Liver Cancer Cells to Chemotherapy by Inhibiting DNA Damage Response in Mouse Xenograft Models

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