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Transformer 2 alpha homolog (TRA2A), a member of the serine/arginine‐rich splicing factor family, has been shown to control mRNA splicing in development and cancers. However, it remains unclear whether TRA2A is involved in lncRNA regulation. In the present study, we found that TRA2A was upregulated and correlated with poor prognosis in esophageal cancer. Downregulation of TRA2A suppressed the tumor growth in xenograft nude mice. Epitranscriptomic microarray showed that depletion of TRA2A affected global lncRNA methylation similarly to the key m6A methyltransferase, METTL3, by silencing. MeRIP‐qPCR, RNA pull‐down, CLIP analyses, and stability assays indicated that ablation of TRA2A reduced m6A‐modification of the oncogenic lncRNA MALAT1, thus inducing structural alterations and reduced stability. Furthermore, Co‐IP experiments showed TRA2A directly interacted with METTL3 and RBMX, which also affected the writer KIAA1429 expression. Knockdown of TRA2A inhibited cell proliferation in a manner restored by RBMX/KIAA1429 overexpression. Clinically, MALAT1, RBMX, and KIAA1429 were prognostic factors of worse survival in ESCA patients. Structural similarity‐based virtual screening in FDA‐approved drugs repurposed nebivolol, a β1‐adrenergic receptor antagonist, as a potent compound to suppress the proliferation of esophageal cancer cells. Cellular thermal shift and RIP assay indicated that nebivolol may compete with MALAT1 to bind TRA2A. In conclusion, our study revealed the noncanonical function of TRA2A, which coordinates with multiple methylation proteins to promote oncogenic MALAT1 during ESCA carcinogenesis. [ABSTRACT FROM AUTHOR]

Recent advances have highlighted the important roles of long non‑coding RNAs (lncRNAs) in a number of biological processes, including oncogenesis. However, the function of lncRNA cartilage injury‑related (lncRNA‑CIR) in bladder cancer progression remains elusive. A novel function for lncRNA‑CIR in bladder cancer was identified in the present study. Reverse transcription quantitative polymerase chain reaction, viability, invasion assay and in vivo implantation were used to evaluate the role of lncRNA‑CIR. It was identified that the expression of lncRNA‑CIR was frequently upregulated in 52 cancerous tissues and selected bladder cancer cell lines. Additionally, upregulating lncRNA‑CIR was demonstrated to promote viability and invasion in T24 and SW780 cells, whereas siRNA‑mediated lncRNA‑CIR‑knockdown consistently exhibited the opposite effects. High lncRNA‑CIR levels also dictated poor overall survival among patients with bladder cancer. Furthermore, in vivo implantation experiments also supported a tumorigenic function for lncRNA‑CIR, as decreasing lncRNA‑CIR levels markedly attenuated Ki‑67 staining and xenograft tumor growth. Overall, the present study identified a novel function of lncRNA‑CIR and indicates that lncRNA‑CIR may serve as a potential biomarker for bladder cancer treatment. [ABSTRACT FROM AUTHOR]

Transformer 2 alpha homolog (TRA2A), a member of the serine/arginine-rich splicing factor family, has been shown to control mRNA splicing in development and cancers. However, it remains unclear whether TRA2A is involved in lncRNA regulation. In the present study, we found that TRA2A was upregulated and correlated with poor prognosis in esophageal cancer. Downregulation of TRA2A suppressed the tumor growth in xenograft nude mice. Epitranscriptomic microarray showed that depletion of TRA2A affected global lncRNA methylation similarly to the key m 6 A methyltransferase, METTL3, by silencing. MeRIP-qPCR, RNA pull-down, CLIP analyses, and stability assays indicated that ablation of TRA2A reduced m 6 A-modification of the oncogenic lncRNA MALAT1, thus inducing structural alterations and reduced stability. Furthermore, Co-IP experiments showed TRA2A directly interacted with METTL3 and RBMX, which also affected the writer KIAA1429 expression. Knockdown of TRA2A inhibited cell proliferation in a manner restored by RBMX/KIAA1429 overexpression. Clinically, MALAT1, RBMX, and KIAA1429 were prognostic factors of worse survival in ESCA patients. Structural similarity-based virtual screening in FDA-approved drugs repurposed nebivolol, a β 1 -adrenergic receptor antagonist, as a potent compound to suppress the proliferation of esophageal cancer cells. Cellular thermal shift and RIP assay indicated that nebivolol may compete with MALAT1 to bind TRA2A. In conclusion, our study revealed the noncanonical function of TRA2A, which coordinates with multiple methylation proteins to promote oncogenic MALAT1 during ESCA carcinogenesis., (© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

The RNA binding protein (RBP) and non-coding RNA (ncRNA) interacting networks are increasingly recognized as the main mechanism in gene regulation, and are tightly associated with cellular malfunction and disease. Here, we present f RNC, a systems biology tool to uncover the dynamic spectrum of RBP-ncRNA circuits (RNC) by integrating transcriptomics, interactomics and proteomics data. f RNC constructs the RBP-ncRNA network derived from CLIP-seq or PARE experiments. Given scoring on nodes and edges according to differential analysis of expression data, it finds an RNC containing global maximum significant RBPs and ncRNAs. Alternatively, it can also capture the locally maximum scoring RNC according to user-defined starting nodes with the greedy search. When compared with existing tools, f RNC can detect more accurate and robust sub-network with scalability. As shown in the cases of esophageal carcinoma, breast cancer and Alzheimer's disease, f RNC enables users to analyze the collective behaviors between RBP and the interacting ncRNAs, and reveal novel insights into the disease-associated processes. The f RNC R package is available at https://github.com/BioinformaticsSTU/ f RNC., Competing Interests: There are no conflicts of interest., (© 2023 The Authors.)

Circular RNAs (circRNAs) are endogenous non-coding RNAs that regulate gene expression and participate in carcinogenesis. However, the RNA-binding proteins (RBPs) involved in circRNAs biogenesis and modulation remain largely unclear. We developed the circRNA regulator identification tool (CRIT), a non-negative matrix-factorization-based pipeline to identify regulating RBPs in cancers. CRIT uncovered 73 novel regulators across thousands of samples by effectively leveraging genomics data and functional annotations. We demonstrated that known RBPs involved in circRNA control are significantly enriched in these predictions. Analysis of circRNA-RBP interactions using two large cross-linking immunoprecipitation (CLIP) databases, we validated the consistency between CRIT prediction and the CLIP experiments. Furthermore, newly discovered RBPs are functionally connected with authentic circRNA regulators by various biological associations, such as physical interaction, similar binding motifs, common transcription factor modulation, and co-expression. When analyzing RNA sequencing (RNA-seq) datasets after short hairpin RNA (shRNA)/small interfering RNA (siRNA) knockdown, we found several novel RBPs that can affect global circRNA expression, which strengthens their role in the circRNA life cycle. The above evidence provided independent confirmation that CRIT is a useful tool to capture RBPs in circRNA processing. Finally, we show that authentic regulators are more likely the core splicing proteins and peripheral factors and usually harbor more alterations in the vast majority of cancers., Competing Interests: The authors declare no competing interests., (© 2022 The Authors.)