Targeting the XPO1-dependent nuclear export of E2F7 reverses anthracycline resistance in head and neck squamous cell carcinomas

Saenz-Ponce, Natalia; Pillay, Rachael Rohini; Long, Lilia Merida de; Kashyap, Trinayan; Argueta, Christian; Landesman, Yosef; Hazar-Rethinam, Mehlika; Boros, Samuel; Panizza, Benedict; Jacquemyn, Maarten; Daelemans, Dirk; Gannon, Orla M.; Saunders, Nicholas A.

doi:10.1126/scitranslmed.aar7223

Cited by 31 publications

(21 citation statements)

References 44 publications

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“…30,31 Recently, direct pharmacological inhibition of XPO1 has been shown to be effective in several types of cancers. [32][33][34][35] XPO1 also has been demonstrated to interact with polyglutamine (polyQ) proteins that are produced from expanded nucleotide repeats in disorders such as Huntington's. 36 Some amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients also have expansion repeats in the ATXN2 gene that result in the production of polyQ proteins.…”

Section: Introductionmentioning

confidence: 99%

The SINE Compound KPT-350 Blocks Dystrophic Pathologies in DMD Zebrafish and Mice

et al. 2020

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Duchenne muscular dystrophy (DMD) is an X-linked muscle wasting disease that is caused by the loss of functional dystrophin protein in cardiac and skeletal muscles. DMD patient muscles become weakened, leading to eventual myofiber breakdown and replacement with fibrotic and adipose tissues. Inflammation drives the pathogenic processes through releasing inflammatory cytokines and other factors that promote skeletal muscle degeneration and contributing to the loss of motor function. Selective inhibitors of nuclear export (SINEs) are a class of compounds that function by inhibiting the nuclear export protein exportin 1 (XPO1). The XPO1 protein is an important regulator of key inflammatory and neurological factors that drive inflammation and neurotoxicity in various neurological and neuromuscular diseases. Here, we demonstrate that SINE compound KPT-350 can ameliorate dystrophic-associated pathologies in the muscles of DMD models of zebrafish and mice. Thus, SINE compounds are a promising novel strategy for blocking dystrophic symptoms and could be used in combinatorial treatments for DMD.

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Section: Introductionmentioning

confidence: 99%

The SINE Compound KPT-350 Blocks Dystrophic Pathologies in DMD Zebrafish and Mice

et al. 2020

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“…Indeed, the features of a drug-resistant breast cancer cell line were assessed by genomic approaches and MDR1 overexpression, together with miRNA-mediated TP53INP1 down-regulation, were found [59]. In addition, two other predicted targets of those miRs, NCKAP1 and E2F7, were previously associated with metastization and drug resistance, respectively [60,61].…”

Section: Discussionmentioning

confidence: 99%

Deep Sequencing Analysis Reveals Distinctive Non-Coding RNAs When Comparing Tumor Multidrug-Resistant Cells and Extracellular Vesicles with Drug-Sensitive Counterparts

Sousa

Matthiesen

Lima

et al. 2020

Cancers

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Multidrug resistance (MDR) is one of the main limitations of cancer treatment. The overexpression of drug-efflux pumps, such as P-glycoprotein (P-gp), is a major cause of MDR. Importantly, different studies have shown that extracellular vesicles (EVs) participate in the communication between MDR cells and drug-sensitive counterparts, promoting dissemination of the MDR phenotype. In the present work, we aimed to identify RNA species present in MDR cells and in EVs released by those cells, which may be associated with the MDR phenotype. The RNA content from two pairs (leukemia and lung cancer) of MDR (P-gp overexpressing) cells and their drug-sensitive counterparts, as well as from their EVs, was analyzed by deep sequencing. Our results showed distinctive transcripts for MDR cells and their EVs, when compared with their drug-sensitive counterparts. Remarkably, two pseudogenes (a novel pseudogene and RNA 5.8S ribosomal pseudogene 2) were found to be increased in EVs released by MDR cells in both leukemia and lung cancer models. Moreover, six miRs (miR-204-5p, miR-139-5p, miR-29c-5p, miR-551b-3p, miR-29b-2-5p, and miR-204-3p) exhibited altered levels in lung cancer MDR cells and their EVs. This study provides insights into the contribution of EVs to MDR.

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“…The global E2F signature is associated with clinical outcomes of patients with pancreatic adenocarcinoma (13). Restoring the balance between E2F1 and E2F7 is a therapeutic strategy in head and neck squamous cell carcinomas (14). These findings indicate the universal functions of the E2F family genes in the development of cancer.…”

Section: Introductionmentioning

confidence: 92%

“…However, previous studies on the E2F family genes have focused on a single E2F gene in a limited number of cancer types (8)(9)(10)(11)(12)(13)(14). Therefore, there is an urgent need to comprehensively analyze E2F family genes across tumor types.…”

Section: Introductionmentioning

confidence: 99%

Integrated analysis of the E2F transcription factors across cancer types

Wang

et al. 2020

Oncol Rep

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E2F transcription factors are associated with the development of cancer. However, the E2F family genes have not yet been studied in a comprehensive manner. Using The Cancer Genome Atlas, the present study analyzed the functions of the E2F family genes across different types of tumor. It was revealed that compared with normal tissues, the E2F family genes are highly expressed in several types of tumor tissue. Furthermore, E2F transcription factors were significantly enriched in tumor samples across different types of tumor. The high expression levels of E2F family genes were associated with an unfavorable prognosis in liver hepatocellular carcinoma (LIHC) and lung adenocarcinoma (LUAD). Furthermore, patients with pathological T1 stage and iCluster2 molecular subtype of LIHC expressed particularly low levels of E2F family genes. The present study demonstrated that hypo-DNA methylation, DNA amplification and TP53 mutation contributed to the high expression levels of E2F family genes in cancer cells. Finally, the present study revealed that, compared with other types of tumor, the E2F family genes were specifically downregulated in patients with LIHC. The expression levels and prognostic effects of the E2F family genes were validated using the Gene Expression Omnibus database. The results of the present study revealed the biological functions of E2F family genes in the development of cancer and provided potential biomarkers for further therapeutic studies, particularly for patients with LIHC and LUAD.

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Targeting the XPO1-dependent nuclear export of E2F7 reverses anthracycline resistance in head and neck squamous cell carcinomas

Cited by 31 publications

References 44 publications

The SINE Compound KPT-350 Blocks Dystrophic Pathologies in DMD Zebrafish and Mice

The SINE Compound KPT-350 Blocks Dystrophic Pathologies in DMD Zebrafish and Mice

Deep Sequencing Analysis Reveals Distinctive Non-Coding RNAs When Comparing Tumor Multidrug-Resistant Cells and Extracellular Vesicles with Drug-Sensitive Counterparts

Integrated analysis of the E2F transcription factors across cancer types

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