Effect of circular RNAs and N6-methyladenosine (m6A) modification on cancer biology

Zhang, Gong; Hou, Junhui; Mei, Chenxue; Wang, Xia; Wang, Yuan; Wang, Kefeng

doi:10.1016/j.biopha.2023.114260

Cited by 12 publications

(6 citation statements)

References 119 publications

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“…The m6A modification is linked to the whole life cycles of RNAs [ 31 ], and may promote the degradation or increase the stability of some circRNAs. For example, circQSOX1 could be m6A modified by METTL3, and further read by IGF2BP2, and knockdown of METTL3 or IGF2BP2 significantly decreased circQSOX1 [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

N6-methyladenosine-modified circRIMS2 mediates synaptic and memory impairments by activating GluN2B ubiquitination in Alzheimer's disease

Wang,

Xie,

Tan

et al. 2023

Transl Neurodegener

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Background Synaptic degeneration occurs in the early stage of Alzheimer's disease (AD) before devastating symptoms, strongly correlated with cognitive decline. Circular RNAs (circRNAs) are abundantly enriched in neural tissues, and aberrant expression of circRNAs precedes AD symptoms, significantly correlated with clinical dementia severity. However, the direct relationship between circRNA dysregulation and synaptic impairment in the early stage of AD remains poorly understood. Methods Hippocampal whole-transcriptome sequencing was performed to identify dysregulated circRNAs and miRNAs in 4-month-old wild-type and APP/PS1 mice. RNA antisense purification and mass spectrometry were utilized to unveil interactions between circRIMS2 and methyltransferase 3, N6-adenosine-methyltransferase complex catalytic subunit (METTL3). The roles of circRIMS2/miR-3968 in synaptic targeting of UBE2K-mediated ubiquitination of GluN2B subunit of NMDA receptor were evaluated via numerous lentiviruses followed by morphological staining, co-immunoprecipitation and behavioral testing. Further, a membrane-permeable peptide was used to block the ubiquitination of K1082 on GluN2B in AD mice. Results circRIMS2 was significantly upregulated in 4-month-old APP/PS1 mice, which was mediated by METTL3-dependent N6-methyladenosine (m6A) modification. Overexpression of circRIMS2 led to synaptic and memory impairments in 4-month-old C57BL/6 mice. MiR-3968/UBE2K was validated as the downstream of circRIMS2. Elevated UBE2K induced synaptic dysfunction of AD through ubiquitinating K1082 on GluN2B. Silencing METTL3 or blocking the ubiquitination of K1082 on GluN2B with a short membrane-permeable peptide remarkably rescued synaptic dysfunction in AD mice. Conclusions In conclusion, our study demonstrated that m6A-modified circRIMS2 mediates the synaptic and memory impairments in AD by activating the UBE2K-dependent ubiquitination and degradation of GluN2B via sponging miR-3968, providing novel therapeutic strategies for AD.

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Section: Discussionmentioning

confidence: 99%

N6-methyladenosine-modified circRIMS2 mediates synaptic and memory impairments by activating GluN2B ubiquitination in Alzheimer's disease

Wang,

Xie,

Tan

et al. 2023

Transl Neurodegener

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“…CircRNAs can be a novel type of therapeutic targets, by functioning as tumor suppressors or oncogenes ( He et al, 2021 ; Pan et al, 2023 ). Accumulated studies have revealed that cancer cells could release circRNAs to the surrounding recipient cells via exosome-mediated transport strategies, thus affecting the carcinogenesis and therapeutic response ( Liu et al, 2021b ; Fontemaggi et al, 2021 ; Zhang et al, 2023 ). For example, the synthetic tumor-suppressing circRNAs can be packaged into exosomes and transported into certain target cells to suppress cancer metastasis and invasion ( Dai et al, 2020 ).…”

Section: Discussion and Perspectivementioning

confidence: 99%

Unraveling the significance of exosomal circRNAs in cancer therapeutic resistance

Kang

Yan²,

Liu³

et al. 2023

Front. Pharmacol.

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Exosomes are nanoscale extracellular vesicles secreted by a variety of cells, affecting the physiological and pathological homeostasis. They carry various cargoes including proteins, lipids, DNA, and RNA and have emerged as critical mediators of intercellular communication. During cell–cell communication, they can internalize either by autologous or heterologous recipient cells, which activate different signaling pathways, facilitating malignant progression of cancer. Among different types of cargoes in exosomes, the endogenous non-coding RNAs, such as circular RNAs (or circRNAs), have gained tremendous attention for their high stability and concentration, playing promising functional roles in cancer chemotherapeutic response by regulating the targeted gene expression. In this review, we primarily described the emerging evidence demonstrating the important roles of circular RNAs derived from exosomes in the regulation of cancer-associated signaling pathways that were involved in cancer research and therapeutic interventions. Additionally, the relevant profiles of exosomal circRNAs and their biological implications have been discussed, which is under investigation for their potential effect on the control of cancer therapeutic resistance.

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“…Prostate cancer progression is facilitated by PDHA1-mediated mitochondrial respiration regulation through m6A-modified circRBM33 [ 62 ]. This suggests that m6A-modified circRNAs could play a crucial role in various cancers by modulating tumor growth, invasion, and progression, with implications for immune regulation, T cell activation, and immune surveillance [ 63 , 64 , 65 , 66 ]. METTL3, part of the m6A methyltransferase complex, enhances the expression of immune costimulatory molecules, thereby stimulating T cell activation [ 64 ].…”

Section: Circrna Regulation Of T Cells In Cancermentioning

confidence: 99%

CircRNA Regulation of T Cells in Cancer: Unraveling Potential Targets

Li,

Yin,

Yang

et al. 2024

IJMS

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T lymphocytes play a critical role in antitumor immunity, but their exhaustion poses a significant challenge for immune evasion by malignant cells. Circular RNAs (circRNAs), characterized by their covalently closed looped structure, have emerged as pivotal regulators within the neoplastic landscape. Recent studies have highlighted their multifaceted roles in cellular processes, including gene expression modulation and protein function regulation, which are often disrupted in cancer. In this review, we systematically explore the intricate interplay between circRNAs and T cell modulation within the tumor microenvironment. By dissecting the regulatory mechanisms through which circRNAs impact T cell exhaustion, we aim to uncover pathways crucial for immune evasion and T cell dysfunction. These insights can inform innovative immunotherapeutic strategies targeting circRNA-mediated molecular pathways. Additionally, we discuss the translational potential of circRNAs as biomarkers for therapeutic response prediction and as intervention targets. Our comprehensive analysis aims to enhance the understanding of immune evasion dynamics in the tumor microenvironment by facilitating the development of precision immunotherapy.

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Effect of circular RNAs and N6-methyladenosine (m6A) modification on cancer biology

Cited by 12 publications

References 119 publications

N6-methyladenosine-modified circRIMS2 mediates synaptic and memory impairments by activating GluN2B ubiquitination in Alzheimer's disease

N6-methyladenosine-modified circRIMS2 mediates synaptic and memory impairments by activating GluN2B ubiquitination in Alzheimer's disease

Unraveling the significance of exosomal circRNAs in cancer therapeutic resistance

CircRNA Regulation of T Cells in Cancer: Unraveling Potential Targets

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