We describe the landscape of somatic genomic alterations based on multidimensional and comprehensive characterization of more than 500 glioblastoma tumors (GBMs). We identify several novel mutated genes as well as complex rearrangements of signature receptors, including EGFR and PDGFRA. TERT promoter mutations are shown to correlate with elevated mRNA expression, supporting a role in telomerase reactivation. Correlative analyses confirm that the survival advantage of the proneural subtype is conferred by the G-CIMP phenotype, and MGMT DNA methylation may be a predictive biomarker for treatment response only in classical subtype GBM. Integrative analysis of genomic and proteomic profiles challenges the notion of therapeutic inhibition of a pathway as an alternative to inhibition of the target itself. These data will facilitate the discovery of therapeutic and diagnostic target candidates, the validation of research and clinical observations and the generation of unanticipated hypotheses that can advance our molecular understanding of this lethal cancer.

The somatic genomic landscape of glioblastoma

Rapid improvements in sequencing and array-based platforms are resulting in a flood of diverse genome-wide data, including data from exome and whole-genome sequencing, epigenetic surveys, expression profiling of coding and noncoding RNAs, single nucleotide polymorphism (SNP) and copy number profiling, and functional assays. Analysis of these large, diverse data sets holds the promise of a more comprehensive understanding of the genome and its relation to human disease. Experienced and knowledgeable human review is an essential component of this process, complementing computational approaches. This calls for efficient and intuitive visualization tools able to scale to very large data sets and to flexibly integrate multiple data types, including clinical data. However, the sheer volume and scope of data pose a significant challenge to the development of such tools.

Integrative Genomics Viewer

Recently, more than 1000 large intergenic noncoding RNAs (lincRNAs) have been reported. These RNAs are evolutionarily conserved in mammalian genomes and thus presumably function in diverse biological processes. Here, we report the identification of lincRNAs that are regulated by p53. One of these lincRNAs (lincRNA-p21) serves as a repressor in p53-dependent transcriptional responses. Inhibition of lincRNA-p21 affects the expression of hundreds of gene targets enriched for genes normally repressed by p53. The observed transcriptional repression by lincRNA-p21 is mediated through the physical association with hnRNP-K. This interaction is required for proper genomic localization of hnRNP-K at repressed genes and regulation of p53 mediates apoptosis. We propose a model whereby transcription factors activate lincRNAs that serve as key repressors by physically associating with repressive complexes and modulate their localization to sets of previously active genes.

A Large Intergenic Noncoding RNA Induced by p53 Mediates Global Gene Repression in the p53 Response

From a Novel

N6-methyladenosine (m6A) is methylation that occurs in the N6-position of adenosine, which is the most prevalent internal modification on eukaryotic mRNA. Accumulating evidence suggests that m6A modulates gene expression, thereby regulating cellular processes ranging from cell self-renewal, differentiation, invasion and apoptosis. M6A is installed by m6A methyltransferases, removed by m6A demethylases and recognized by reader proteins, which regulate of RNA metabolism including translation, splicing, export, degradation and microRNA processing. Alteration of m6A levels participates in cancer pathogenesis and development via regulating expression of tumor-related genes like BRD4, MYC, SOCS2 and EGFR. In this review, we elaborate on recent advances in research of m6A enzymes. We also highlight the underlying mechanism of m6A in cancer pathogenesis and progression. Finally, we review corresponding potential targets in cancer therapy.

/pdf/functions-of-n6-methyladenosine-and-its-role-in-cancer-2mbjjwdcui.pdf

Functions of N6-methyladenosine and its role in cancer.

Covalently closed single-stranded circular RNAs (circRNAs) consist of introns or exons and are widely present in eukaryotic cells. CircRNAs generally have low expression levels and relatively stable structures compared with messenger RNAs (mRNAs), most of which are located in the cytoplasm and often act in cell type and tissue-specific manners, indicating that they may serve as novel biomarkers. In recent years, circRNAs have gradually become a hotspot in the field of RNA and cancer research, but the functions of most circRNAs have not yet been discovered. Known circRNAs can affect the biogenesis of cancers in diverse ways, such as functioning as a microRNA (miRNA) sponges, combining with RNA binding proteins (RBPs), working as a transcription factor and translation of proteins. In this review, we summarize the characteristics and types of circRNAs, introduce the biogenesis of circRNAs, discuss the emerging functions and databases on circRNAs and present the current challenges of circRNAs studies.

/pdf/the-novel-roles-of-circrnas-in-human-cancer-tdz0m9wcar.pdf

The novel roles of circRNAs in human cancer

N6-methyladenosine (m6A), the most prevalent modification of mammalian RNA, has received increasing attention. Although m6A has been shown to be associated with biological activities, such as spermatogenesis modulation, cell spermatogenesis and pluripotency, Drosophila sex determination, and the control of T cell homeostasis and response to heat shock, little is known about its roles in cancer biology and cancer stem cells. Recent articles have noted that some genes have abnormal m6A expression after tumorigenesis, including genes ABS2, RARA, MYB, MYC, ADAM19 and FOX1. Abnormal changes in the m6A levels of these genes are closely related to tumour occurrence and development. In this review, we summarized the ‘dual edge weapon’ role of RNA methylation in the tumorigenesis. We discussed RNA methylation could lead to not only tumour progression but also tumour suppression. Moreover, we clarified that the abnormal changes in the m6A enrichment of specific loci contribute to tumour occurrence and development, thereby representing a novel anti-cancer strategy by restoration to balanced RNA methylation in tumour cells.

/pdf/novel-insights-on-m-6-a-rna-methylation-in-tumorigenesis-a-5ek6ypbvj9.pdf

Novel insights on m 6 A RNA methylation in tumorigenesis: a double-edged sword.

Histone lactylation, a metabolic stress-related histone modification, plays an important role in the regulation of gene expression during M1 macrophage polarization. However, the role of histone lactylation in tumorigenesis remains unclear. Here, we show histone lactylation is elevated in tumors and is associated with poor prognosis of ocular melanoma. Target correction of aberrant histone lactylation triggers therapeutic efficacy both in vitro and in vivo. Mechanistically, histone lactylation contributes to tumorigenesis by facilitating YTHDF2 expression. Moreover, YTHDF2 recognizes the m6A modified PER1 and TP53 mRNAs and promotes their degradation, which accelerates tumorigenesis of ocular melanoma. We reveal the oncogenic role of histone lactylation, thereby providing novel therapeutic targets for ocular melanoma therapy. We also bridge histone modifications with RNA modifications, which provides novel understanding of epigenetic regulation in tumorigenesis.

/pdf/histone-lactylation-drives-oncogenesis-by-facilitating-m-6-a-1r0snzmmuq.pdf

Histone lactylation drives oncogenesis by facilitating m 6 A reader protein YTHDF2 expression in ocular melanoma

Objective: To explore the presence and characteristics of FoxP3‐expressing CD4+CD25+ regulatory T cells in synovial fluid (SF) of patients with active rheumatoid arthritis (RA).Methods: The frequency and chemokine receptors expression profile of FoxP3‐expressing CD4+CD25+ regulatory T cells in SF and peripheral blood (PB) from RA patients and PB from healthy controls were investigated by flow cytometry using three‐ or four‐colour intracellular staining.Results: The frequency of CD4+CD25+ FoxP3+ T cells was increased significantly in SF compared with paired PB from RA patients and PB from healthy controls (p<0.05). However, the frequency in PB from RA patients was significantly lower than in PB from healthy controls (p<0.05). Notably, CD4+CD25+FoxP3+ T cells in SF expressed increased levels of inflammation‐related trafficking chemokine receptors, such as CCR4, CCR5, and CXCR4.Conclusion: There is an accumulation of FoxP3‐expressing regulatory T cells in RA SF, and such recruitment may be dependent on the d...

Accumulation of FoxP3-expressing CD4+CD25+ T cells with distinct chemokine receptors in synovial fluid of patients with active rheumatoid arthritis.

Dynamic N6-methyladenosine (m6A) RNA modification generated and erased by N6-methyltransferases and demethylases regulates gene expression, alternative splicing and cell fate. Ocular melanoma, comprising uveal melanoma (UM) and conjunctival melanoma (CM), is the most common primary eye tumor in adults and the 2nd most common melanoma. However, the functional role of m6A modification in ocular melanoma remains unclear. m6A assays and survival analysis were used to explore decreased global m6A levels, indicating a late stage of ocular melanoma and a poor prognosis. Multiomic analysis of miCLIP-seq, RNA-seq and Label-free MS data revealed that m6A RNA modification posttranscriptionally promoted HINT2 expression. RNA immunoprecipitation (RIP)-qPCR and dual luciferase assays revealed that HINT2 mRNA specifically interacted with YTHDF1. Furthermore, polysome profiling analysis indicated a greater amount of HINT2 mRNA in the translation pool in ocular melanoma cells with higher m6A methylation. Here, we show that RNA methylation significantly inhibits the progression of UM and CM. Ocular melanoma samples showed decreased m6A levels, indicating a poor prognosis. Changes in global m6A modification were highly associated with tumor progression in vitro and in vivo. Mechanistically, YTHDF1 promoted the translation of methylated HINT2 mRNA, a tumor suppressor in ocular melanoma. Our work uncovers a critical function for m6A methylation in ocular melanoma and provides additional insight into the understanding of m6A modification.

/pdf/m6a-modification-suppresses-ocular-melanoma-through-2mpvf3ewnq.pdf

Renbing Jia

Papers

The novel roles of circRNAs in human cancer

Novel insights on m 6 A RNA methylation in tumorigenesis: a double-edged sword.

Histone lactylation drives oncogenesis by facilitating m 6 A reader protein YTHDF2 expression in ocular melanoma

Accumulation of FoxP3-expressing CD4+CD25+ T cells with distinct chemokine receptors in synovial fluid of patients with active rheumatoid arthritis.

m6A modification suppresses ocular melanoma through modulating HINT2 mRNA translation.