Subcellular localization of FANCD2 is associated with survival in ovarian carcinoma

Joshi, Sonali; Campbell, Shawn; Lim, Jeong Youn; McWeeney, Shannon K.; Krieg, Adam J.; Bean, Yukie T.; Pejovic, Nadja; Mhawech‐Fauceglia, Paulette; Pejović, Tanja

doi:10.18632/oncotarget.27437

Cited by 10 publications

(7 citation statements)

References 41 publications

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“…Previous studies have linked Fancd2 to susceptibility to cancer. Fancd2 is a key player in the DNA repair pathway and is important for maintaining genomic stability in response to various gene damage [ 13 ]. Recently, there are studies that up-regulation of Fancd2 expression is positively correlated with tumor size and poor prognosis in ovarian cancer, nasopharyngeal carcinoma, glioblastoma, and EC [ 19 ].…”

Section: Discussionmentioning

confidence: 99%

“…Lisa et al observed that high expression of Fancd2 promoted excessive proliferation and metastasis of esophageal squamous cell carcinoma cells [ 12 ]. Sonali et al suggested a correlation between subcellular localization of Fancd2 and ovarian cancer survival; and Fancd2 localized in the nucleus led to reduced patient survival [ 13 ]. Collectively, the role of Fancd2 in cancers is evident.…”

Section: Introductionmentioning

confidence: 99%

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Fanconi anemia complementation group D2 promotes sensitivity of endometrial cancer cells to chemotherapeutic agents by inhibiting the ferroptosis pathway

Lin,

Zeng,

Yang

et al. 2024

BMC Women's Health

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Background Resistance can develop during treatment of advanced endometrial cancer (EC), leading to unsatisfactory results. Fanconi anemia complementation group D2 (Fancd2) has been shown to be closely related to drug resistance in cancer cells. Therefore, this study was designed to explore the correlation of Fancd2 with EC resistance and the mechanism of Fancd2. Methods Real-time quantitative PCR (RT-qPCR) was used to detect the expression of Fancd2 in EC tissues and cells. EC cells (Ishikawa) and paclitaxel-resistant EC cells (Ishikawa/TAX) were transfected to knock down Fancd2. In addition, the ferroptosis inhibitor Ferrostatin-1 was adopted to treat Ishikawa/TAX cells. The sensitivity of cancer cells to chemotherapeutic agents was observed via 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay, and inhibitory concentration (IC)50 was calculated. Reactive oxygen species (ROS) levels were measured by flow cytometry, the activity of malondialdehyde (MDA) and the levels of glutathione (GSH) and Fe2+ in cells were detected by corresponding kits, and protein expression of solute farrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) was obtained through western blot. Results Compared with the normal tissues and endometrial epithelial cells, Fancd2 expression was significantly increased in EC tissues and Ishikawa cells, respectively. After knock-down of Fancd2, Ishikawa cells showed significantly increased sensitivity to chemotherapeutic agents. Besides, compared with Ishikawa cells, the levels of ROS, the activity of MDA, and the levels of GSH and Fe2+ were significantly decreased in Ishikawa/TAX cells, while the expression levels of SLC7A11 and GPX4 were significantly increased. Knock-down of Fancd2 significantly increased the ferroptosis levels in Ishikawa/TAX cells, but this effect could be reversed by Ferrostatin-1. Conclusion Fancd2 increases drug resistance in EC cells by inhibiting the cellular ferroptosis pathway.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Fanconi anemia complementation group D2 promotes sensitivity of endometrial cancer cells to chemotherapeutic agents by inhibiting the ferroptosis pathway

Lin,

Zeng,

Yang

et al. 2024

BMC Women's Health

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“…Since ATM is a DDR gene and functions through the phosphorylation of HRR-associated genes, namely ATR , RAD51 , FANCD2 , RPA2 , and BRCA1/2 among others [ 39 – 43 ], we investigated the expression of various HRR-associated genes and γH2AX in ATM -KO NGP and ATM haploinsufficient CHP-134 cells. We observed that the protein levels of FANCD2, RAD51, and ATR, which promote alternative end-joining, DNA damage repair, and cancer cell survival [ 44 , 45 ], were downregulated. In contrast, p21 and γH2AX levels increased in the ATM -deficient NB cells (Fig.…”

Section: Discussionmentioning

confidence: 99%

ATM depletion induces proteasomal degradation of FANCD2 and sensitizes neuroblastoma cells to PARP inhibitors

et al. 2023

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Background Genomic alterations, including loss of function in chromosome band 11q22-23, are frequently observed in neuroblastoma, which is the most common extracranial childhood tumour. In neuroblastoma, ATM, a DNA damage response-associated gene located on 11q22-23, has been linked to tumorigenicity. Genetic changes in ATM are heterozygous in most tumours. However, it is unclear how ATM is associated with tumorigenesis and cancer aggressiveness. Methods To elucidate its molecular mechanism of action, we established ATM-inactivated NGP and CHP-134 neuroblastoma cell lines using CRISPR/Cas9 genome editing. The knock out cells were rigorously characterized by analyzing proliferation, colony forming abilities and responses to PARP inhibitor (Olaparib). Western blot analyses were performed to detect different protein expression related to DNA repair pathway. ShRNA lentiviral vectors were used to knockdown ATM expression in SK-N-AS and SK-N-SH neuroblastoma cell lines. ATM knock out cells were stably transfected with FANCD2 expression plasmid to over-expressed the FANCD2. Moreover, knock out cells were treated with proteasome inhibitor MG132 to determine the protein stability of FANCD2. FANCD2, RAD51 and γH2AX protein expressions were determined by Immunofluorescence microscopy. Results Haploinsufficient ATM resulted in increased proliferation (p < 0.01) and cell survival following PARP inhibitor (olaparib) treatment. However, complete ATM knockout decreased proliferation (p < 0.01) and promoted cell susceptibility to olaparib (p < 0.01). Complete loss of ATM suppressed the expression of DNA repair-associated molecules FANCD2 and RAD51 and induced DNA damage in neuroblastoma cells. A marked downregulation of FANCD2 expression was also observed in shRNA-mediated ATM-knockdown neuroblastoma cells. Inhibitor experiments demonstrated that the degradation of FANCD2 was regulated at the protein level through the ubiquitin–proteasome pathway. Reintroduction of FANCD2 expression is sufficient to reverse decreased proliferation mediated by ATM depletion. Conclusions Our study revealed the molecular mechanism underlying ATM heterozygosity in neuroblastomas and elucidated that ATM inactivation enhances the susceptibility of neuroblastoma cells to olaparib treatment. These findings might be useful in the treatment of high-risk NB patients showing ATM zygosity and aggressive cancer progression in future.

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“…Also, studies conducted in the United Kingdom and Poland on ovarian carcinoma samples verified that the risk of recurrence and death are highly associated with the expression level of FANCD2 (Moes-Sosnowska, 2019; Mani, 2021). On the other hand, in the United States, a study conducted on 181 ovarian cancer patients provided evidence of an increased survival rate in patients with FANCD2 mutation (Joshi, 2020). On the basis of its upregulation, FANCD2 has an unsatisfactory prognosis for other types of cancer, which may contribute to tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

Next-generation DNA sequencing identifies mutated FANCD2 Gene as a novel Biomarker for monitoring early disease progression and timely therapeutic interventions in advanced phase Chronic Myeloid Leukemia patients

Alanazi,

Siyal,

Absar

et al. 2023

Preprint

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Chronic Myeloid Leukemia, resulting due to chromosomal aberration t(9;22) through formation of oncogenic BCR-ABL fusion oncogene. Modern BCR-ABL inhibitors, called TKIs, have revolutionized CML treatment. CML has three stages: chronic, accelerated, and blast crisis. TKIs work well in CP-CML, where patients survive as long as the normal population, but they don’t work in AP- and BC-CML. Even with advances in treatment, BC-CML has an average overall survival of less than a year, giving oncologists little time to clinically intervene. Oncologists can delay or prevent CML advancement by detecting patients at risk of disease progression early and making timely treatment decisions, especially with third and fourth generation TKIs. However, no universal molecular biomarkers exist to diagnose CML patient groups at risk of disease progression.A recent study found that all BC-CML patients have mutant FANCD2. Our study was designed to detect mutant FANCD2 in AP-CML (early progression phase) to investigate its potential as a novel biomarker of early CML progression from chronic phase to accelerated phase due to the urgent need for such a biomarker.Our study comprised of 123 CP-CML (control group) and 60 AP-CML patients (as experimental group) from Hayatabad Medical Complex, Peshawar, Pakistan, from Jan 2020 to July 2023. DNA was extracted from the patients and FANCD2 gene was sequenced using Illumina next generation sequencer (NGS) Illumina MiSeq sequencer. NGS analysis revealed a unique splice site mutation in FANCD2 gene (c. 2022-5C>T). This mutation was detected in all CP-CML patients but in none of CP-CML. The mutation was confirmed by Sanger sequencing.FANCD2 is member of Fanconi anemia (FA-) pathway gene involved in DNA repair and genomic instability. Therefore, our studies show that FANCD2 (c. 2022-5C>T) mutation as a very specific molecular biomarker for early CML progression. We recommend to clinical validate this biomarker is prospective clinical trials.

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Subcellular localization of FANCD2 is associated with survival in ovarian carcinoma

Cited by 10 publications

References 41 publications

Fanconi anemia complementation group D2 promotes sensitivity of endometrial cancer cells to chemotherapeutic agents by inhibiting the ferroptosis pathway

Fanconi anemia complementation group D2 promotes sensitivity of endometrial cancer cells to chemotherapeutic agents by inhibiting the ferroptosis pathway

ATM depletion induces proteasomal degradation of FANCD2 and sensitizes neuroblastoma cells to PARP inhibitors

Next-generation DNA sequencing identifies mutated FANCD2 Gene as a novel Biomarker for monitoring early disease progression and timely therapeutic interventions in advanced phase Chronic Myeloid Leukemia patients

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