Detecting and Characterizing A-to-I MicroRNA Editing in Cancer

Adenosine to inosine (A-to-I) editing consists of an RNA modification where single adenosines along the RNA sequence are converted into inosines. Such a biochemical transformation is catalyzed by enzymes belonging to the family of adenosine deaminases acting on RNA (ADARs) and occurs either co- or post-transcriptionally. The employment of powerful, high-throughput detection methods has recently revealed that A-to-I editing widely occurs in non-coding RNAs, including microRNAs (miRNAs). MiRNAs are a class of small regulatory non-coding RNAs (ncRNAs) acting as translation inhibitors, known to exert relevant roles in controlling cell cycle, proliferation, and cancer development. Indeed, a growing number of recent researches have evidenced the importance of miRNA editing in cancer biology by exploiting various detection and validation methods. Herein, we briefly overview early and currently available A-to-I miRNA editing detection and validation methods and discuss the significance of A-to-I miRNA editing in human cancer.

Download Full-text

Main N6-Methyladenosine Readers: YTH Family Proteins in Cancers

Frontiers in Oncology ◽

10.3389/fonc.2021.635329 ◽

2021 ◽

Vol 11 ◽

Author(s):

Xin-Yuan Dai ◽

Liang Shi ◽

Zhi Li ◽

Hai-Yan Yang ◽

Ji-Fu Wei ◽

...

Keyword(s):

Cancer Therapy ◽

Rna Splicing ◽

Mammalian Cells ◽

Biological Function ◽

Human Cancer ◽

Messenger Rnas ◽

Rna Modifications ◽

Reversible Process ◽

Rna Export ◽

Non Coding Rnas

Among the over 150 RNA modifications, N6-methyladenosine (m6A) is the most abundant internal modification in eukaryotic RNAs, not only in messenger RNAs, but also in microRNAs and long non-coding RNAs. It is a dynamic and reversible process in mammalian cells, which is installed by “writers,” consisting of METTL3, METTL14, WTAP, RBM15/15B, and KIAA1429 and removed by “erasers,” including FTO and ALKBH5. Moreover, m6A modification is recognized by “readers,” which play the key role in executing m6A functions. IYT521-B homology (YTH) family proteins are the first identified m6A reader proteins. They were reported to participate in cancer tumorigenesis and development through regulating the metabolism of targeted RNAs, including RNA splicing, RNA export, translation, and degradation. There are many reviews about function of m6A and its role in various diseases. However, reviews only focusing on m6A readers, especially YTH family proteins are few. In this review, we systematically summarize the recent advances in structure and biological function of YTH family proteins, and their roles in human cancer and potential application in cancer therapy.

Download Full-text

Comprehensive database and evolutionary dynamics of U12-type introns

Nucleic Acids Research ◽

10.1093/nar/gkaa464 ◽

2020 ◽

Cited By ~ 3

Author(s):

Devlin C Moyer ◽

Graham E Larue ◽

Courtney E Hershberger ◽

Scott W Roy ◽

Richard A Padgett

Keyword(s):

Rna Splicing ◽

Evolutionary Dynamics ◽

Messenger Rnas ◽

Spliceosomal Introns ◽

Conversion Model ◽

Nuclear Maturation ◽

Small Nuclear Ribonucleoprotein ◽

Associated Proteins ◽

Non Coding Rnas ◽

Nuclear Ribonucleoprotein

Abstract During nuclear maturation of most eukaryotic pre-messenger RNAs and long non-coding RNAs, introns are removed through the process of RNA splicing. Different classes of introns are excised by the U2-type or the U12-type spliceosomes, large complexes of small nuclear ribonucleoprotein particles and associated proteins. We created intronIC, a program for assigning intron class to all introns in a given genome, and used it on 24 eukaryotic genomes to create the Intron Annotation and Orthology Database (IAOD). We then used the data in the IAOD to revisit several hypotheses concerning the evolution of the two classes of spliceosomal introns, finding support for the class conversion model explaining the low abundance of U12-type introns in modern genomes.

Download Full-text

MiREDiBase, a manually curated database of validated and putative editing events in microRNAs

Scientific Data ◽

10.1038/s41597-021-00979-8 ◽

2021 ◽

Vol 8 (1) ◽

Author(s):

Gioacchino P. Marceca ◽

Rosario Distefano ◽

Luisa Tomasello ◽

Alessandro Lagana ◽

Francesco Russo ◽

...

Keyword(s):

Rna Editing ◽

Cell Biology ◽

Enrichment Analysis ◽

Minimum Free Energy ◽

Binding Ability ◽

Cellular Processes ◽

Non Coding Rnas ◽

Target Binding ◽

And Function ◽

Mirna Editing

AbstractMicroRNAs (miRNAs) are regulatory small non-coding RNAs that function as translational repressors. MiRNAs are involved in most cellular processes, and their expression and function are presided by several factors. Amongst, miRNA editing is an epitranscriptional modification that alters the original nucleotide sequence of selected miRNAs, possibly influencing their biogenesis and target-binding ability. A-to-I and C-to-U RNA editing are recognized as the canonical types, with the A-to-I type being the predominant one. Albeit some bioinformatics resources have been implemented to collect RNA editing data, it still lacks a comprehensive resource explicitly dedicated to miRNA editing. Here, we present MiREDiBase, a manually curated catalog of editing events in miRNAs. The current version includes 3,059 unique validated and putative editing sites from 626 pre-miRNAs in humans and three primates. Editing events in mature human miRNAs are supplied with miRNA-target predictions and enrichment analysis, while minimum free energy structures are inferred for edited pre-miRNAs. MiREDiBase represents a valuable tool for cell biology and biomedical research and will be continuously updated and expanded at https://ncrnaome.osumc.edu/miredibase.

Download Full-text

Updated Database and Evolutionary Dynamics of U12-Type Introns

10.1101/620658 ◽

2019 ◽

Author(s):

Devlin C. Moyer ◽

Graham E. Larue ◽

Courtney E. Hershberger ◽

Scott W. Roy ◽

Richard A. Padgett

Keyword(s):

Rna Splicing ◽

Evolutionary Dynamics ◽

Messenger Rnas ◽

Spliceosomal Introns ◽

Conversion Model ◽

Nuclear Maturation ◽

Small Nuclear Ribonucleoprotein ◽

Associated Proteins ◽

Non Coding Rnas ◽

Nuclear Ribonucleoprotein

ABSTRACTDuring nuclear maturation of most eukaryotic pre-messenger RNAs and long non-coding RNAs, introns are removed through the process of RNA splicing. Different classes of introns are excised by the U2-type or the U12-type spliceosomes, large complexes of small nuclear ribonucleoprotein particles and associated proteins. We created intronIC, a program for assigning intron class to all introns in a given genome, and used it on 24 eukaryotic genomes to create the Intron Annotation and Orthology Database (IAOD). We then used the data in the IAOD to revisit several hypotheses concerning the evolution of the two classes of spliceosomal introns, finding support for the class conversion model explaining the low abundance of U12-type introns in modern genomes.

Download Full-text

MiREDiBase: a manually curated database of validated and putative editing events in microRNAs

10.1101/2020.09.04.283689 ◽

2020 ◽

Author(s):

Gioacchino P. Marceca ◽

Rosario Distefano ◽

Luisa Tomasello ◽

Alessandro Lagana ◽

Francesco Russo ◽

...

Keyword(s):

Rna Editing ◽

Cell Biology ◽

Enrichment Analysis ◽

Minimum Free Energy ◽

Binding Ability ◽

Cellular Processes ◽

Non Coding Rnas ◽

Target Binding ◽

And Function ◽

Mirna Editing

AbstractMicroRNAs (miRNAs) are regulatory small non-coding RNAs that function as translational repressors. MiRNAs are involved in most cellular processes, and their expression and function are presided by several factors. Amongst, miRNA editing is an epitranscriptional modification that alters the original nucleotide sequence of selected miRNAs, possibly influencing their biogenesis and target-binding ability. A-to-I and C-to-U RNA editing are recognized as the canonical types, with the A-to-I type being the predominant one. Albeit some bioinformatics resources have been implemented to collect RNA editing data, it still lacks a comprehensive resource explicitly dedicated to miRNA editing. Here, we present MiREDiBase, a manually curated catalog of editing events in miRNAs. The current version includes 3,059 unique validated and putative editing sites from 626 pre-miRNAs in humans and three primates. Editing events in mature human miRNAs are supplied with miRNA-target predictions and enrichment analysis, while minimum free energy structures are inferred for edited pre-miRNAs. MiREDiBase represents a valuable tool for cell biology and biomedical research and will be continuously updated and expanded at https://ncrnaome.osumc.edu/miredibase.

Download Full-text

Epigenetic loss of the transfer RNA-modifying enzyme TYW2 induces ribosome frameshifts in colon cancer

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2003358117 ◽

2020 ◽

Vol 117 (34) ◽

pp. 20785-20793 ◽

Cited By ~ 4

Author(s):

Margalida Rosselló-Tortella ◽

Pere Llinàs-Arias ◽

Yuriko Sakaguchi ◽

Kenjyo Miyauchi ◽

Veronica Davalos ◽

...

Keyword(s):

Colon Cancer ◽

Cancer Biology ◽

Human Cancer ◽

Early Stage ◽

Protein Translation ◽

Promoter Hypermethylation ◽

Transfer Rna ◽

Messenger Rnas ◽

Epigenetic Changes ◽

Poor Overall Survival

Transfer RNA (tRNA) activity is tightly regulated to provide a physiological protein translation, and tRNA chemical modifications control its function in a complex with ribosomes and messenger RNAs (mRNAs). In this regard, the correct hypermodification of position G37 of phenylalanine-tRNA, adjacent to the anticodon, is critical to prevent ribosome frameshifting events. Here we report that the tRNA-yW Synthesizing Protein 2 (TYW2) undergoes promoter hypermethylation-associated transcriptional silencing in human cancer, particularly in colorectal tumors. The epigenetic loss of TYW2 induces guanosine hypomodification in phenylalanine-tRNA, an increase in −1 ribosome frameshift events, and down-regulation of transcripts by mRNA decay, such as of the key cancer gene ROBO1. Importantly, TYW2 epigenetic inactivation is linked to poor overall survival in patients with early-stage colorectal cancer, a finding that could be related to the observed acquisition of enhanced migration properties and epithelial-to-mesenchymal features in the colon cancer cells that harbor TYW2 DNA methylation-associated loss. These findings provide an illustrative example of how epigenetic changes can modify the epitranscriptome and further support a role for tRNA modifications in cancer biology.

Download Full-text

Mechanistic Roles of Noncoding RNAs in Lung Cancer Biology and Their Clinical Implications

Genetics Research International ◽

10.1155/2012/737416 ◽

2012 ◽

Vol 2012 ◽

pp. 1-16 ◽

Cited By ~ 23

Author(s):

Katey S. S. Enfield ◽

Larissa A. Pikor ◽

Victor D. Martinez ◽

Wan L. Lam

Keyword(s):

Lung Cancer ◽

Rna Splicing ◽

Cancer Biology ◽

Noncoding Rnas ◽

Protein Coding ◽

Cellular Processes ◽

Protein Coding Genes ◽

Non Coding Rnas ◽

Clinical Potential

Lung cancer biology has traditionally focused on genomic and epigenomic deregulation of protein-coding genes to identify oncogenes and tumor suppressors diagnostic and therapeutic targets. Another important layer of cancer biology has emerged in the form of noncoding RNAs (ncRNAs), which are major regulators of key cellular processes such as proliferation, RNA splicing, gene regulation, and apoptosis. In the past decade, microRNAs (miRNAs) have moved to the forefront of ncRNA cancer research, while the role of long noncoding RNAs (lncRNAs) is emerging. Here we review the mechanisms by which miRNAs and lncRNAs are deregulated in lung cancer, the technologies that can be applied to detect such alterations, and the clinical potential of these RNA species. An improved comprehension of lung cancer biology will come through the understanding of the interplay between deregulation of non-coding RNAs, the protein-coding genes they regulate, and how these interactions influence cellular networks and signalling pathways.

Download Full-text

Prostate Cancer: Biology, Incidence, Detection Methods, Treatment Methods, and Vaccines

Current Topics in Medicinal Chemistry ◽

10.2174/1568026620666200224100730 ◽

2020 ◽

Vol 20 (10) ◽

pp. 847-854

Author(s):

Ronald Bartzatt

Keyword(s):

Prostate Cancer ◽

Cancer Treatment ◽

Prostate Specific Antigen ◽

Cancer Biology ◽

Early Stage ◽

Specific Antigen ◽

Detection Methods ◽

Hormone Refractory Prostate Cancer ◽

High Risk Prostate Cancer ◽

Hormone Refractory

Cancer of the prostate are cancers in which most incidences are slow-growing, and in the U.S., a record of 1.2 million new cases of prostate cancer occurred in 2018. The rates of this type of cancer have been increasing in developing nations. The risk factors for prostate cancer include age, family history, and obesity. It is believed that the rate of prostate cancer is correlated with the Western diet. Various advances in methods of radiotherapy have contributed to lowering morbidity. Therapy for hormone- refractory prostate cancer is making progress, for almost all men with metastases will proceed to hormone-refractory prostate cancer. Smoking cigarettes along with the presence of prostate cancer has been shown to cause a higher risk of mortality in prostate cancer. The serious outcome of incontinence and erectile dysfunction result from the cancer treatment of surgery and radiation, particularly for prostate- specific antigen detected cancers that will not cause morbidity or mortality. Families of patients, as well as patients, are profoundly affected following the diagnosis of prostate cancer. Poor communication between spouses during prostate cancer increases the risk for poor adjustment to prostate cancer. The use of serum prostate-specific antigen to screen for prostate cancer has led to a greater detection, in its early stage, of this cancer. Prostate cancer is the most common malignancy in American men, accounting for more than 29% of all diagnosed cancers and about 13% of all cancer deaths. A shortened course of hormonal therapy with docetaxel following radical prostatectomy (or radiation therapy) for high-risk prostate cancer has been shown to be both safe and feasible. Patients treated with docetaxel-estramustine had a prostate-specific antigen response decline of at least 50%. Cancer vaccines are an immune-based cancer treatment that may provide the promise of a non-toxic but efficacious therapeutic alternative for cancer patients. Further studies will elucidate improved methods of detection and treatment.

Download Full-text

Novel insights into the m6A-RNA methyltransferase METTL3 in cancer

Biomarker Research ◽

10.1186/s40364-021-00278-9 ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Yiqing Cai ◽

Rui Feng ◽

Tiange Lu ◽

Xiaomin Chen ◽

Xiangxiang Zhou ◽

...

Keyword(s):

Poor Prognosis ◽

Human Cancer ◽

Rna Modification ◽

Rapid Progression ◽

Antitumor Therapy ◽

Promoting Effect ◽

Methyl Group ◽

Group Transfer ◽

Functional Regulation ◽

Methyl Group Transfer

AbstractN6-methyladenosine (m6A) is a prevalent internal RNA modification in higher eukaryotic cells. As the pivotal m6A regulator, RNA methyltransferase-like 3 (METTL3) is responsible for methyl group transfer in the progression of m6A modification. This epigenetic regulation contributes to the structure and functional regulation of RNA and further promotes tumorigenesis and tumor progression. Accumulating evidence has illustrated the pivotal roles of METTL3 in a variety of human cancers. Here, we systemically summarize the interaction between METTL3 and RNAs, and illustrate the multiple functions of METTL3 in human cancer. METLL3 is aberrantly expressed in a variety of tumors. Elevation of METTL3 is usually associated with rapid progression and poor prognosis of tumors. On the other hand, METTL3 may also function as a tumor suppressor in several cancers. Based on the tumor-promoting effect of METTL3, the possibility of applying METTL3 inhibitors is further discussed, which is expected to provide novel insights into antitumor therapy.

Download Full-text