Novel insights into the interplay between m6A modification and noncoding RNAs in cancer

Yi, You-Cai; Chen, Xiaoyu; Zhang, Jing; Zhu, Jingde

doi:10.1186/s12943-020-01233-2

Cited by 181 publications

(170 citation statements)

References 120 publications

(163 reference statements)

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“…Recent studies have discovered a number of lncRNAs modified by N(6)-methyladenosine in multiple cancers, and they can regulate gene expression and function through a series of complex mechanisms [ 37 – 42 ]. In turn, lncRNAs can target or modulate N(6)-methyladenosine regulators to influence the development of cancer [ 43 ]. However, the role of lncRNAs in the N(6)-methyladenosine modification of rRNA remains unknown.…”

Section: Discussionmentioning

confidence: 99%

RETRACTED ARTICLE: Downregulation of lncRNA ZNF582-AS1 due to DNA hypermethylation promotes clear cell renal cell carcinoma growth and metastasis by regulating the N(6)-methyladenosine modification of MT-RNR1

Yang

Zhang

et al. 2021

J Exp Clin Cancer Res

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Background Emerging evidence confirms that lncRNAs (long non-coding RNAs) are potential biomarkers that play vital roles in tumors. ZNF582-AS1 is a novel lncRNA that serves as a potential prognostic marker of cancers. However, the specific clinical significance and molecular mechanism of ZNF582-AS1 in ccRCC (clear cell renal cell carcinoma) are unclear. Methods Expression level and clinical significance of ZNF582-AS1 were determined by TCGA-KIRC data and qRT-PCR results of 62 ccRCCs. DNA methylation status of ZNF582-AS1 promoter was examined by MSP, MassARRAY methylation and demethylation analysis. Gain-of-function experiments were conducted to investigate the biological roles of ZNF582-AS1 in the phenotype of ccRCC. The subcellular localization of ZNF582-AS1 was detected by RNA FISH. iTRAQ, RNA pull-down and RIP-qRT-PCR were used to identify the downstream targets of ZNF582-AS1. rRNA MeRIP-seq and MeRIP-qRT-PCR were utilized to examine the N(6)-methyladenosine modification status. Western blot and immunohistochemistry assays were used to determine the protein expression level. Results ZNF582-AS1 was downregulated in ccRCC, and decreased ZNF582-AS1 expression was significantly correlated with advanced tumor stage, higher pathological stage, distant metastasis and poor prognosis. Decreased ZNF582-AS1 expression was caused by DNA methylation at the CpG islands within its promoter. ZNF582-AS1 overexpression inhibited cell proliferative, migratory and invasive ability, and increased cell apoptotic rate in vitro and in vivo. Mechanistically, we found that ZNF582-AS1 overexpression suppressed the N(6)-methyladenosine modification of MT-RNR1 by reducing rRNA adenine N(6)-methyltransferase A8K0B9 protein level, resulting in the decrease of MT-RNR1 expression, followed by the inhibition of MT-CO2 protein expression. Furthermore, MT-RNR1 overexpression reversed the decreased MT-CO2 expression and phenotype inhibition of ccRCC induced by increased ZNF582-AS1 expression. Conclusions This study demonstrates for the first time that ZNF582-AS1 functions as a tumor suppressor gene in ccRCC and ZNF582-AS1 may serve as a potential biomarker and therapeutic target of ccRCC.

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Section: Discussionmentioning

confidence: 99%

RETRACTED ARTICLE: Downregulation of lncRNA ZNF582-AS1 due to DNA hypermethylation promotes clear cell renal cell carcinoma growth and metastasis by regulating the N(6)-methyladenosine modification of MT-RNR1

Yang

Zhang

et al. 2021

J Exp Clin Cancer Res

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“…Obesity-associated protein (FTO) and alkB homolog 5 (ALKBH5) stimulate the demethylation process and are included under “eraser” complex ( 15 , 16 ). Extensive studies on m6A modification indicated toward its contribution in regulation of mRNA ( 17 ), long non-coding RNA (lncRNA) ( 18 ), microRNA ( 19 ), and circular RNA (circRNA) ( 20 ). m6A modification being an important RNA regulatory mechanism has been proved to play a critical role in regulating RNA processing, transportation, translation, and decay.…”

Section: Introductionmentioning

confidence: 99%

The Impact of m6A RNA Modification in Therapy Resistance of Cancer: Implication in Chemotherapy, Radiotherapy, and Immunotherapy

et al. 2021

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m6A RNA methylation, which serves as a critical regulator of transcript expression, has gathered tremendous scientific interest in recent years. From RNA processing to nuclear export, RNA translation to decay, m6A modification has been studied to affect various aspects of RNA metabolism, and it is now considered as one of the most abundant epitranscriptomic modification. RNA methyltransferases (writer), m6A-binding proteins (readers), and demethylases (erasers) proteins are frequently upregulated in several neoplasms, thereby regulating oncoprotein expression, augmenting tumor initiation, enhancing cancer cell proliferation, progression, and metastasis. Though the potential role of m6A methylation in growth and proliferation of cancer cells has been well documented, its potential role in development of therapy resistance in cancer is not clear. In this review, we focus on m6A-associated regulation, mechanisms, and functions in acquired chemoresistance, radioresistance, and resistance to immunotherapy in cancer.

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“…Similarly, we also found that ALKBH5 could increase NANOG expression in glioma. Moreover, the m6A modi cation may be addressed by noncoding RNA [21]. Apart from the direct interaction of miR-1252-5p and 3'UTR of NANOG, we also found that miR-1252-5p could bind with 3'UTR of ALKBH5.…”

Section: Discussionmentioning

confidence: 69%

“…NANOG contributes to tumor cell growth and TMZ resistance in glioma [19,20]. N6-methyladenosine (m6A) is a common mRNA modi cation, and it is involved in the regulation of noncoding RNAs on tumorigenesis [21].AlkB homolog H5 (ALKBH5) is a representative m6A demethylase which can lead to the demethylation of mRNA in human disease [22]. ALKBH5 maintains tumorigenicity of glioma stem-like cells [23].…”

Section: Introductionmentioning

confidence: 99%

Warburg Effect-Promoted Exosomal Circ_0072083 Releasing Up-Regulates Nango Expression Through Multiple Pathways and Enhances Temozolomide Resistance in Glioma

Ding

Chen

et al. 2020

Preprint

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BackgroundTemozolomide (TMZ) resistance limits its application in glioma. Exosome can carry circular RNAs (circRNAs) to regulate drug resistance via sponging microRNAs (miRNAs). miRNAs can control mRNA expression by regulate the interaction with 3’UTR and methylation. Nanog homeobox (NANOG) is an important biomarker for TMZ resistance. Hitherto, it is unknown about the role of exosomal hsa_circ_0072083 (circ_0072083) in TMZ resistance in glioma, and whether it is associated with NANOG via regulating miRNA sponge and methylation.MethodsTMZ-resistant (n=36) and sensitive (n=33) patients were recruited. The sensitive cells and constructed resistant cells were cultured and exposed to TMZ. circ_0072083, miR-1252-5p, AlkB homolog H5 (ALKBH5) and NANOG levels were examined via quantitative reverse transcription polymerase chain reaction and western blot. The half maximal inhibitory concentration (IC50) of TMZ, cell proliferation, apoptosis, migration and invasion were analyzed via Cell Counting Kit-8, colony formation, flow cytometry, wound healing and transwell assays. The in vivo function was assessed using xenograft model. The N6-methyladenosine (m6A) level was analyzed via methylated RNA immunoprecipitation (MeRIP). Target relationship was investigated via dual-luciferase reporter assay and RNA immunoprecipitation. Warburg effect was investigated via lactate production, glucose uptake and key enzymes expression. Exosome was isolated and confirmed via transmission electron microscopy and specific protein expression.Resultscirc_0072083 expression was increased in TMZ-resistant glioma tissues and cells. circ_0072083 knockdown restrained the resistance of resistant cells via decreasing IC50 of TMZ, proliferation, migration, invasion and xenograft tumor growth and increasing apoptosis. circ_0072083 silence reduced NANOG expression via blocking ALKBH5-mediated demethylation. circ_0072083 could regulate NANOG and ALKBH5 via targeting miR-1252-5p to control TMZ resistance. Warburg effect promoted the release of exosomal circ_0072083 in resistant cells. Exosomal circ_0072083 from resistant cells increased the resistance of sensitive cells to TMZ in vitro and xenograft model. Exosomal circ_0072083 level was enhanced in resistant patients, and it had a diagnostic value and indicated a lower overall survival in glioma. ConclusionExosomal circ_0072083 promoted TMZ resistance via increasing NANOG via regulating miR-1252-5p-mediated degradation and demethylation in glioma.

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Novel insights into the interplay between m6A modification and noncoding RNAs in cancer

Cited by 181 publications

References 120 publications

RETRACTED ARTICLE: Downregulation of lncRNA ZNF582-AS1 due to DNA hypermethylation promotes clear cell renal cell carcinoma growth and metastasis by regulating the N(6)-methyladenosine modification of MT-RNR1

RETRACTED ARTICLE: Downregulation of lncRNA ZNF582-AS1 due to DNA hypermethylation promotes clear cell renal cell carcinoma growth and metastasis by regulating the N(6)-methyladenosine modification of MT-RNR1

The Impact of m6A RNA Modification in Therapy Resistance of Cancer: Implication in Chemotherapy, Radiotherapy, and Immunotherapy

Warburg Effect-Promoted Exosomal Circ_0072083 Releasing Up-Regulates Nango Expression Through Multiple Pathways and Enhances Temozolomide Resistance in Glioma

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