From General Aberrant Alternative Splicing in Cancers and Its Therapeutic Application to the Discovery of an Oncogenic DMTF1 Isoform

Tian, Na; Li, Jialiang; Shi, Jinming; Sui, Guangchao

doi:10.3390/ijms18030191

Cited by 16 publications

(18 citation statements)

References 106 publications

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“…Recognition of the splicing affecting variants is beneficial not only for the diagnostics, but it may eventually lead to the development of effective RNA-targeting therapy. This issue has been addressed by several recent reviews [ 65 , 66 , 67 , 68 ].…”

Section: Clinical Significance Of Splicing Aberrationsmentioning

confidence: 99%

Mutations of Pre-mRNA Splicing Regulatory Elements: Are Predictions Moving Forward to Clinical Diagnostics?

Grodecká

Buratti

Freiberger

2017

IJMS

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For more than three decades, researchers have known that consensus splice sites alone are not sufficient regulatory elements to provide complex splicing regulation. Other regulators, so-called splicing regulatory elements (SREs) are needed. Most importantly, their sequence variants often underlie the development of various human disorders. However, due to their variable location and high degeneracy, these regulatory sequences are also very difficult to recognize and predict. Many different approaches aiming to identify SREs have been tried, often leading to the development of in silico prediction tools. While these tools were initially expected to be helpful to identify splicing-affecting mutations in genetic diagnostics, we are still quite far from meeting this goal. In fact, most of these tools are not able to accurately discern the SRE-affecting pathological variants from those not affecting splicing. Nonetheless, several recent evaluations have given appealing results (namely for EX-SKIP, ESRseq and Hexplorer predictors). In this review, we aim to summarize the history of the different approaches to SRE prediction, and provide additional validation of these tools based on patients’ clinical data. Finally, we evaluate their usefulness for diagnostic settings and discuss the challenges that have yet to be met.

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Section: Clinical Significance Of Splicing Aberrationsmentioning

confidence: 99%

Mutations of Pre-mRNA Splicing Regulatory Elements: Are Predictions Moving Forward to Clinical Diagnostics?

Grodecká

Buratti

Freiberger

2017

IJMS

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“…found that DMTF1β, a major subtype of DMTFs, was overexpressed in breast cancer tissues and promotes tumorigenesis in a transgenic mouse model [45]. Niklaus et al indicated the cisplatin resistance of breast cancer cells is associated with expression of DMTF1-β by using SKBR3 (cisplatin sensitive) and MCF7 (cisplatin resistant) breast cancer cell lines in vitro [46].…”

Section: Discussionmentioning

confidence: 99%

Identification of Potential Prognostic Biomarkers for Breast Cancer Based on lncRNA-TF-Associated ceRNA Network and Functional Module

Zhu

Qiu

2020

BioMed Research International

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Breast cancer leads to most of cancer deaths among women worldwide. Systematically analyzing the competing endogenous RNA (ceRNA) network and their functional modules may provide valuable insight into the pathogenesis of breast cancer. In this study, we constructed a lncRNA-TF-associated ceRNA network via combining all the significant lncRNA-TF ceRNA pairs and TF-TF PPI pairs. We computed important topological features of the network, such as degree and average path length. Hub nodes in the lncRNA-TF-associated ceRNA network were extracted to detect differential expression in different subtypes and tumor stages of breast cancer. MCODE was used for identifying the closely connected modules from the ceRNA network. Survival analysis was further used for evaluating whether the modules had prognosis effects on breast cancer. TF motif searching analysis was performed for investigating the binding potentials between lncRNAs and TFs. As a result, a lncRNA-TF-associated ceRNA network in breast cancer was constructed, which had a scale-free property. Hub nodes such as MDM4, ZNF410, AC0842-19, and CTB-89H12 were differentially expressed between cancer and normal sample in different subtypes and tumor stages. Two closely connected modules were identified to significantly classify patients into a low-risk group and high-risk group with different clinical outcomes. TF motif searching analysis suggested that TFs, such as NFAT5, might bind to the promoter and enhancer regions of hub lncRNAs and function in breast cancer biology. The results demonstrated that the synergistic, competitive lncRNA-TF ceRNA network and their functional modules played important roles in the biological processes and molecular functions of breast cancer.

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“…Another example is represented by the Dmtf gene, which physiologically controls the Arf-p53 pathway, through transactivation of the Cdkn2a (p14ARF) promoter and physical interaction with p53. The DMTF1β isoform that lacks the C-terminal TAD and the DNA binding ability of the full-length α isoform is overexpressed and associated with poor patient outcomes in breast cancer and contributes to human leukemogenesis [119][120][121].…”

Section: Dns With Altered Regultory Abilitymentioning

confidence: 99%

Transcription Factors in Cancer: When Alternative Splicing Determines Opposite Cell Fates

Belluti

Rigillo

Imbriano

2020

Cells

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Alternative splicing (AS) is a finely regulated mechanism for transcriptome and proteome diversification in eukaryotic cells. Correct balance between AS isoforms takes part in molecular mechanisms that properly define spatiotemporal and tissue specific transcriptional programs in physiological conditions. However, several diseases are associated to or even caused by AS alterations. In particular, multiple AS changes occur in cancer cells and sustain the oncogenic transcriptional program. Transcription factors (TFs) represent a key class of proteins that control gene expression by direct binding to DNA regulatory elements. AS events can generate cancer-associated TF isoforms with altered activity, leading to sustained proliferative signaling, differentiation block and apoptosis resistance, all well-known hallmarks of cancer. In this review, we focus on how AS can produce TFs isoforms with opposite transcriptional activities or antagonistic functions that severely impact on cancer biology. This summary points the attention to the relevance of the analysis of TFs splice variants in cancer, which can allow patients stratification despite the presence of interindividual genetic heterogeneity. Recurrent TFs variants that give advantage to specific cancer types not only open the opportunity to use AS transcripts as clinical biomarkers but also guide the development of new anti-cancer strategies in personalized medicine.

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From General Aberrant Alternative Splicing in Cancers and Its Therapeutic Application to the Discovery of an Oncogenic DMTF1 Isoform

Cited by 16 publications

References 106 publications

Mutations of Pre-mRNA Splicing Regulatory Elements: Are Predictions Moving Forward to Clinical Diagnostics?

Mutations of Pre-mRNA Splicing Regulatory Elements: Are Predictions Moving Forward to Clinical Diagnostics?

Identification of Potential Prognostic Biomarkers for Breast Cancer Based on lncRNA-TF-Associated ceRNA Network and Functional Module

Transcription Factors in Cancer: When Alternative Splicing Determines Opposite Cell Fates

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