scholarly journals Pan-cancer analysis of RNA binding proteins (RBPs) reveals the involvement of the core pre-mRNA splicing and translation machinery in tumorigenesis

2018 ◽  
Author(s):  
Bin Zhang ◽  
Kamesh R. Babu ◽  
Chun You Lim ◽  
Zhi Hao Kwok ◽  
Jia Li ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Copy Number ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Human Cancer ◽  
Mrna Splicing ◽  
Regulatory Mechanisms ◽  
Translation Machinery ◽  
The Core ◽  
Cancer Types

AbstractRNA binding proteins (RBPs) are key regulators of posttranscriptional processes such as RNA maturation, transport, localization, turnover and translation. Despite their dysregulation in various diseases including cancer, the landscape of RBP expression and regulatory mechanisms in human cancer has not been well characterized. Here, we analyzed mRNA expression of 1487 RBPs in ~6700 clinical samples across 16 human cancer types and found that there were significantly more upregulated RBPs than downregulated ones in tumors when compared to their adjacent normal tissues. Across almost all of the 16 cancer types, 109 RBPs were consistently upregulated (cuRBPs) while only 41 RBPs were consistently downregulated (cdRBPs). Integrating expression with the copy number and DNA methylation data, we found that the overexpression of cuRBPs is largely associated with the amplification of copy number, whereas the downregulation of cdRBPs may be a result of epigenetic silencing mediated by DNA methylation. Furthermore, our results indicated that cuRBPs could work together to promote cancer progression potentially through the involvement of splicing and translation machinery, while cdRBPs might function independently to suppress tumorigenesis. Additionally, we focused on colon cancer and identified several novel potential oncogenic RBPs, such as PABPC1L which might promote cancer development via regulating the core splicing machinery. In summary, we showed distinct expression landscapes, regulatory mechanisms and characteristics of cuRBPs and cdRBPs and implicated several novel RBPs in cancer pathogenesis. Moreover, our results suggest that the involvement of the core pre-mRNA splicing and translation machinery could be critical in tumorigenesis.

scholarly journals A comprehensive expression landscape of RNA-binding proteins (RBPs) across 16 human cancer types

RNA Biology ◽  
2019 ◽  
Vol 17 (2) ◽  
pp. 211-226 ◽  
Author(s):  
Bin Zhang ◽  
Kamesh R. Babu ◽  
Chun You Lim ◽  
Zhi Hao Kwok ◽  
Jia Li ◽  
...  
Keyword(s):  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Human Cancer ◽  
Cancer Types

scholarly journals Lin28, a major translation reprogramming factor, gains access to YB-1-packaged mRNA through its cold-shock domain

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Anastasiia Samsonova ◽  
Krystel El Hage ◽  
Bénédicte Desforges ◽  
Vandana Joshi ◽  
Marie-Jeanne Clément ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Cold Shock ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Rna Binding Protein ◽  
Large Set ◽  
Core Component ◽  
The Core ◽  
Cold Shock Domain ◽  
Global Translation

AbstractThe RNA-binding protein Lin28 (Lin28a) is an important pluripotency factor that reprograms translation and promotes cancer progression. Although Lin28 blocks let-7 microRNA maturation, Lin28 also binds to a large set of cytoplasmic mRNAs directly. However, how Lin28 regulates the processing of many mRNAs to reprogram global translation remains unknown. We show here, using a structural and cellular approach, a mixing of Lin28 with YB-1 (YBX1) in the presence of mRNA owing to their cold-shock domain, a conserved β-barrel structure that binds to ssRNA cooperatively. In contrast, the other RNA binding-proteins without cold-shock domains tested, HuR, G3BP-1, FUS and LARP-6, did not mix with YB-1. Given that YB-1 is the core component of dormant mRNPs, a model in which Lin28 gains access to mRNPs through its co-association with YB-1 to mRNA may provide a means for Lin28 to reprogram translation. We anticipate that the translational plasticity provided by mRNPs may contribute to Lin28 functions in development and adaptation of cancer cells to an adverse environment.

scholarly journals Regulatory mechanisms of phosphatase of regenerating liver (PRL)-3

2016 ◽  
Vol 44 (5) ◽  
pp. 1305-1312 ◽  
Author(s):  
Teresa Rubio ◽  
Maja Köhn
Keyword(s):  
Drug Development ◽  
Posttranslational Modifications ◽  
Human Cancer ◽  
Regulatory Mechanisms ◽  
Therapeutic Drug ◽  
Regenerating Liver ◽  
Cancer Types ◽  
Tumor Metastases ◽  
Phosphatase Of Regenerating Liver ◽  
Incomplete Picture

The phosphatase of regenerating liver (PRL)-3 is overexpressed in many human cancer types and tumor metastases when compared with healthy tissues. Different pathways and mechanisms have been suggested to modulate PRL-3 expression levels and activity, giving some valuable insights but still leaving an incomplete picture. Investigating these mechanisms could provide new targets for therapeutic drug development. Here, we present an updated overview and summarize recent findings concerning the different PRL-3 expression regulatory mechanisms and posttranslational modifications suggested to modulate the activity, localization, or stability of this phosphatase.

scholarly journals SAM68: Signal Transduction and RNA Metabolism in Human Cancer

2015 ◽  
Vol 2015 ◽  
pp. 1-14 ◽  
Author(s):  
Paola Frisone ◽  
Davide Pradella ◽  
Anna Di Matteo ◽  
Elisa Belloni ◽  
Claudia Ghigna ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Signal Transduction ◽  
Nuclear Export ◽  
Cell Biology ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Splice Variants ◽  
Human Cancer ◽  
Rna Metabolism ◽  
Regulatory Sequences

Alterations in expression and/or activity of splicing factors as well as mutations incis-acting splicing regulatory sequences contribute to cancer phenotypes. Genome-wide studies have revealed more than 15,000 tumor-associated splice variants derived from genes involved in almost every aspect of cancer cell biology, including proliferation, differentiation, cell cycle control, metabolism, apoptosis, motility, invasion, and angiogenesis. In the past decades, several RNA binding proteins (RBPs) have been implicated in tumorigenesis. SAM68 (SRC associated in mitosis of 68 kDa) belongs to the STAR (signal transduction and activation of RNA metabolism) family of RBPs. SAM68 is involved in several steps of mRNA metabolism, from transcription to alternative splicing and then to nuclear export. Moreover, SAM68 participates in signaling pathways associated with cell response to stimuli, cell cycle transitions, and viral infections. Recent evidence has linked this RBP to the onset and progression of different tumors, highlighting misregulation of SAM68-regulated splicing events as a key step in neoplastic transformation and tumor progression. Here we review recent studies on the role of SAM68 in splicing regulation and we discuss its contribution to aberrant pre-mRNA processing in cancer.

scholarly journals RNA-binding protein SORBS2 suppresses clear cell renal cell carcinoma metastasis by enhancing MTUS1 mRNA stability

2020 ◽  
Vol 11 (12) ◽  
Author(s):  
Qi Lv ◽  
Fan Dong ◽  
Yong Zhou ◽  
Zhiping Cai ◽  
Gangmin Wang
Keyword(s):  
Tumor Suppressor ◽  
Mrna Stability ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Cell Renal Cell Carcinoma ◽  
Renal Cell Carcinoma Metastasis ◽  
Metastatic Capacity ◽  
Cancer Types ◽  
Carcinoma Metastasis ◽  
Ccrcc Cell

AbstractRNA-binding proteins (RBPs) predominantly contribute to abnormal posttranscriptional gene modulation and disease progression in cancer. Sorbin and SH3 domain-containing 2 (SORBS2), an RBP, has been reported to be a potent tumor suppressor in several cancer types. Through integrative analysis of clinical specimens, we disclosed that the expression level of SORBS2 was saliently decreased in metastatic tissues and positively correlated with overall survival. We observed that overexpression of SORBS2 brought about decreased metastatic capacity in ccRCC cell lines. Transcriptome-wide analysis revealed that SORBS2 notably increased microtubule-associated tumor-suppressor 1 gene (MTUS1) expression. In-depth mechanistic exploring discovered that the Cys2-His2 zinc finger (C2H2-ZnF) domain of SORBS2 directly bound to the 3′ untranslated region (3′UTR) of MTUS1 mRNA, which increased MTUS1 mRNA stability. In addition, we identified that MTUS1 regulated microtubule dynamics via promoting KIF2CS192 phosphorylation by Aurora B. Together, our research identified SORBS2 as a suppressor of ccRCC metastasis by enhancing MTUS1 mRNA stability, providing a novel understanding of RBPs during ccRCC progression.

Abstract 5759: The landscape of copy-number changes across multiple human cancer types

2010 ◽  
Author(s):  
Rameen Beroukhim ◽  
Matthew Meyerson ◽  
Levi Garraway ◽  
John Prensner
Keyword(s):  
Copy Number ◽  
Human Cancer ◽  
Cancer Types ◽  
Copy Number Changes

scholarly journals RNA editing in cancer impacts mRNA abundance in immune response pathways

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Tracey W. Chan ◽  
Ting Fu ◽  
Jae Hoon Bahn ◽  
Hyun-Ik Jun ◽  
Jae-Hyung Lee ◽  
...  
Keyword(s):  
Immune Response ◽  
Rna Editing ◽  
Rna Binding ◽  
Epithelial Mesenchymal Transition ◽  
Rna Binding Proteins ◽  
Mrna Abundance ◽  
Mesenchymal Tumors ◽  
Mesenchymal Transition ◽  
Cancer Types ◽  
Experimental Validations

Abstract Background RNA editing generates modifications to the RNA sequences, thereby increasing protein diversity and shaping various layers of gene regulation. Recent studies have revealed global shifts in editing levels across many cancer types, as well as a few specific mechanisms implicating individual sites in tumorigenesis or metastasis. However, most tumor-associated sites, predominantly in noncoding regions, have unknown functional relevance. Results Here, we carry out integrative analysis of RNA editing profiles between epithelial and mesenchymal tumors, since epithelial-mesenchymal transition is a key paradigm for metastasis. We identify distinct editing patterns between epithelial and mesenchymal tumors in seven cancer types using TCGA data, an observation further supported by single-cell RNA sequencing data and ADAR perturbation experiments in cell culture. Through computational analyses and experimental validations, we show that differential editing sites between epithelial and mesenchymal phenotypes function by regulating mRNA abundance of their respective genes. Our analysis of RNA-binding proteins reveals ILF3 as a potential regulator of this process, supported by experimental validations. Consistent with the known roles of ILF3 in immune response, epithelial-mesenchymal differential editing sites are enriched in genes involved in immune and viral processes. The strongest target of editing-dependent ILF3 regulation is the transcript encoding PKR, a crucial player in immune and viral response. Conclusions Our study reports widespread differences in RNA editing between epithelial and mesenchymal tumors and a novel mechanism of editing-dependent regulation of mRNA abundance. It reveals the broad impact of RNA editing in cancer and its relevance to cancer-related immune pathways.

scholarly journals Identification of rare germline copy number variations over-represented in five human cancer types

2015 ◽  
Vol 14 (1) ◽  
Author(s):  
Richard W Park ◽  
Tae-Min Kim ◽  
Simon Kasif ◽  
Peter J Park
Keyword(s):  
Copy Number ◽  
Human Cancer ◽  
Copy Number Variations ◽  
Cancer Types

scholarly journals The Drosophila RNA binding protein Nab2 patterns dendritic arbors and axons via the planar cell polarity pathway

2021 ◽  
Author(s):  
Kenneth H. Moberg ◽  
Edwin B. Corgiat ◽  
Sara List ◽  
J. Christopher Rounds ◽  
Dehong Yu ◽  
...  
Keyword(s):  
Cell Polarity ◽  
Planar Cell Polarity ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Axon Growth ◽  
Planar Cell Polarity Pathway ◽  
Translational Repressor ◽  
The Core ◽  
Dendritic Arbors ◽  
Axon Projection

RNA binding proteins support neurodevelopment by modulating numerous steps in post-transcriptional regulation, including splicing, export, translation, and turnover of mRNAs that can traffic into axons and dendrites. One such RBP is ZC3H14, which is lost in an inherited intellectual disability. The Drosophila melanogaster ZC3H14 ortholog, Nab2, localizes to neuronal nuclei and cytoplasmic ribonucleoprotein granules, and is required for olfactory memory and proper axon projection into brain mushroom bodies. Nab2 can act as a translational repressor in conjunction with the Fragile-X mental retardation protein homolog Fmr1 and shares target RNAs with the Fmr1-interacting RBP Ataxin-2. However, neuronal signaling pathways regulated by Nab2 and their potential roles outside of mushroom body axons remain undefined. Here, we demonstrate that Nab2 restricts branching and projection of larval sensory dendrites via the planar cell polarity pathway, and that this link may provide a conserved mechanism through which Nab2/ZC3H14 modulates projection of both axons and dendrites. Planar cell polarity proteins are enriched in a Nab2-regulated brain proteomic dataset. Complementary genetic data indicate that Nab2 guides dendrite and axon growth through the planar-cell-polarity pathway. Analysis of the core planar cell polarity protein Vang, which is depleted in the Nab2 mutant whole-brain proteome, uncovers selective and dramatic loss of Vang within axon/dendrite-enriched brain neuropil relative to brain regions containing cell bodies. Collectively, these data demonstrate that Nab2 regulates dendritic arbors and axon projection by a planar-cell-polarity-linked mechanism and identify Nab2 as required for accumulation of the core planar cell polarity factor Vang in distal neuronal projections.

scholarly journals Comprehensive Analysis of Co-Mutations Identifies Cooperating Mechanisms of Tumorigenesis

2021 ◽  
Author(s):  
Limin Jiang ◽  
Hui Yu ◽  
Scott Ness ◽  
Peng Mao ◽  
Fei Guo ◽  
...  
Keyword(s):  
Predictive Power ◽  
Drug Sensitivity ◽  
Somatic Mutations ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
P Value ◽  
Micro Rnas ◽  
Cancer Types ◽  
Potential Impact ◽  
Functional Analyses

AbstractSomatic mutations are one of the most important factors in tumorigenesis and are the focus of most cancer sequencing efforts. The co-occurrence of multiple mutations in one tumor has gained increasing attention as a means of identifying cooperating mutations or pathways that contribute to cancer.Using multi-omics, phenotypical, and clinical data from 29,559 cancer subjects and 1,747 cancer cell lines covering 78 distinct cancer types, we show that co-mutations are associated with prognosis, drug sensitivity, and disparities in sex, age, and race. Some co-mutation combinations displayed stronger effects than their corresponding single mutations. For example, co-mutation TP53:KRAS in pancreatic adenocarcinoma is significantly associated with disease specific survival (hazard ratio = 2.87, adjusted p-value = 0.0003) and its prognostic predictive power is greater than either TP53 or KRAS as individually mutated genes. Functional analyses revealed that co-mutations with higher prognostic values have higher potential impact and cause greater dysregulation of gene expression. Furthermore, many of the prognostically significant co-mutations caused gains or losses of binding sequences of RNA binding proteins or micro RNAs with known cancer associations. Thus, detailed analyses of co-mutations can identify mechanisms that cooperate in tumorigenesis.

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