bims-rimeca Biomed News
on RNA methylation in cancer
Issue of 2021–03–28
fiveteen papers selected by
Sk Ramiz Islam, Saha Institute of Nuclear Physics
  1. The crosstalk between m6A RNA methylation and other epigenetic regulators: a novel perspective in epigenetic remodeling.
  2. m6A Regulators Is Differently Expressed and Correlated With Immune Response of Esophageal Cancer.
  3. mTORC1 stimulates cell growth through SAM synthesis and m6A mRNA-dependent control of protein synthesis.
  4. mTORC1 promotes cell growth via m6A-dependent mRNA degradation.
  5. Analysis of m6A-Related Signatures in the Tumor Immune Microenvironment and Identification of Clinical Prognostic Regulators in Adrenocortical Carcinoma.
  6. Emerging Perspectives of RNA N 6-methyladenosine (m6A) Modification on Immunity and Autoimmune Diseases.
  7. METTL3-mediated m6A methylation of SPHK2 promotes gastric cancer progression by targeting KLF2.
  8. N6-methyladenosine-induced circ1662 promotes metastasis of colorectal cancer by accelerating YAP1 nuclear localization.
  9. RNA demethylation by FTO stabilizes the FOXJ1 mRNA for proper motile ciliogenesis.
  10. METTL3 attenuates proliferative vitreoretinopathy and epithelial-mesenchymal transition of retinal pigment epithelial cells via wnt/β-catenin pathway.
  11. Modeling multi-species RNA modification through multi-task curriculum learning.
  12. Dysregulation of LINC00470 and METTL3 promotes chemoresistance and suppresses autophagy of chronic myelocytic leukaemia cells.
  13. N6-Methyladenosine Induced miR-34a-5p Promotes TNF-α-Induced Nucleus Pulposus Cell Senescence by Targeting SIRT1.
  14. N6 -Methyladenosine (m6 A) readers are dysregulated in renal cell carcinoma.
  15. YBX1 is required for maintaining myeloid leukemia cell survival by regulating BCL2 stability in an m6A-dependent manner.
  1. Theranostics. 2021 ;11(9): 4549-4566
    The crosstalk between m6A RNA methylation and other epigenetic regulators: a novel perspective in epigenetic remodeling.
    Yanchun Zhao, Yunhao Chen, Mei Jin, Jin Wang.
      Epigenetic regulation involves a range of sophisticated processes which contribute to heritable alterations in gene expression without altering DNA sequence. Regulatory events predominantly include DNA methylation, chromatin remodeling, histone modifications, non-coding RNAs (ncRNAs), and RNA modification. As the most prevalent RNA modification in eukaryotic cells, N6-methyladenosine (m6A) RNA methylation actively participates in the modulation of RNA metabolism. Notably, accumulating evidence has revealed complicated interrelations occurring between m6A and other well-known epigenetic modifications. Their crosstalk conspicuously triggers epigenetic remodeling, further yielding profound impacts on a variety of physiological and pathological processes, especially tumorigenesis. Herein, we provide an up-to-date review of this emerging hot area of biological research, summarizing the interplay between m6A RNA methylation and other epigenetic regulators, and highlighting their underlying functions in epigenetic reprogramming.
    Keywords:  DNA methylation; N6-methyladenosine (m6A); RNA modification; chromatin remodeling; histone modification; non-coding RNA (ncRNA)
    DOI:  https://doi.org/10.7150/thno.54967
  2. Front Cell Dev Biol. 2021 ;9 650023
    m6A Regulators Is Differently Expressed and Correlated With Immune Response of Esophageal Cancer.
    Huaying Zhao, Yue Xu, Yilin Xie, Lan Zhang, Ming Gao, Shenglei Li, Feng Wang.
      N6 methyladenosine (m6A) RNA methylation regulators play an important role in the development of tumors. However, their function in esophageal cancer (EC) has not been fully elucidated. Here, we analyzed the gene expression data of 24 major m6A RNA methylation regulators from 775 patients with EC from TCGA dataset. The present study showed the aberrations of m6A regulators in genome were correlated to prognosis in human ECs. Meanwhile, 17 m6A regulators showed increased expression in EC samples, including YTHDC1, IGF2BP2, FTO, METTL14, YTHDF3, RBM15, WTAP, HNRNPA2B1, HNRNPC, ALKBH5, YTHDF2, METTL16, IGF2BP3, VIRMA, RBM15B, YTHDF1, KIAA1429, HAKAI, and ZC3H13. Among them, we found HNRNPC, YTHDC2, WTAP, VIRMA, IGF2BP3, and HNRNPA2B1 were significantly correlated to worse outcomes and advanced stage in EC. Furthermore, we showed levels of m6A regulators is correlated with the expression of Immuno-regulators (Immunoinhibitors, Immunostimulators, and MHC molecules) and immune infiltration levels in EC. Bioinformatics further confirm m6A regulators were involved in regulating RNA splicing, RNA stability, and cell proliferation. Our study showed m6A regulators are promising targets and biomarkers for cancer immunotherapy in EC.
    Keywords:  RNA methylation; TCGA; esophageal cancer; immune infiltration; m6A
    DOI:  https://doi.org/10.3389/fcell.2021.650023
  3. Mol Cell. 2021 Mar 17. pii: S1097-2765(21)00177-5. [Epub ahead of print]
    mTORC1 stimulates cell growth through SAM synthesis and m6A mRNA-dependent control of protein synthesis.
    Elodie Villa, Umakant Sahu, Brendan P O'Hara, Eunus S Ali, Kathryn A Helmin, John M Asara, Peng Gao, Benjamin D Singer, Issam Ben-Sahra.
      The mechanistic target of rapamycin complex 1 (mTORC1) regulates metabolism and cell growth in response to nutrient, growth, and oncogenic signals. We found that mTORC1 stimulates the synthesis of the major methyl donor, S-adenosylmethionine (SAM), through the control of methionine adenosyltransferase 2 alpha (MAT2A) expression. The transcription factor c-MYC, downstream of mTORC1, directly binds to intron 1 of MAT2A and promotes its expression. Furthermore, mTORC1 increases the protein abundance of Wilms' tumor 1-associating protein (WTAP), the positive regulatory subunit of the human N6-methyladenosine (m6A) RNA methyltransferase complex. Through the control of MAT2A and WTAP levels, mTORC1 signaling stimulates m6A RNA modification to promote protein synthesis and cell growth. A decline in intracellular SAM levels upon MAT2A inhibition decreases m6A RNA modification, protein synthesis rate, and tumor growth. Thus, mTORC1 adjusts m6A RNA modification through the control of SAM and WTAP levels to prime the translation machinery for anabolic cell growth.
    Keywords:  Cell growth; MAT2A; Methionine cycle; N(6)-methyladenosine; Protein Synthesis; RNA metabolism; S-adenosylmethionine; WTAP; mTOR; mTORC1
    DOI:  https://doi.org/10.1016/j.molcel.2021.03.009
  4. Mol Cell. 2021 Mar 19. pii: S1097-2765(21)00178-7. [Epub ahead of print]
    mTORC1 promotes cell growth via m6A-dependent mRNA degradation.
    Sungyun Cho, Gina Lee, Brian F Pickering, Cholsoon Jang, Jin H Park, Long He, Lavina Mathur, Seung-Soo Kim, Sunhee Jung, Hong-Wen Tang, Sebastien Monette, Joshua D Rabinowitz, Norbert Perrimon, Samie R Jaffrey, John Blenis.
      Dysregulated mTORC1 signaling alters a wide range of cellular processes, contributing to metabolic disorders and cancer. Defining the molecular details of downstream effectors is thus critical for uncovering selective therapeutic targets. We report that mTORC1 and its downstream kinase S6K enhance eIF4A/4B-mediated translation of Wilms' tumor 1-associated protein (WTAP), an adaptor for the N6-methyladenosine (m6A) RNA methyltransferase complex. This regulation is mediated by 5' UTR of WTAP mRNA that is targeted by eIF4A/4B. Single-nucleotide-resolution m6A mapping revealed that MAX dimerization protein 2 (MXD2) mRNA contains m6A, and increased m6A modification enhances its degradation. WTAP induces cMyc-MAX association by suppressing MXD2 expression, which promotes cMyc transcriptional activity and proliferation of mTORC1-activated cancer cells. These results elucidate a mechanism whereby mTORC1 stimulates oncogenic signaling via m6A RNA modification and illuminates the WTAP-MXD2-cMyc axis as a potential therapeutic target for mTORC1-driven cancers.
    Keywords:  MXD2; Protein translation; S6K1; WTAP; YTHDF readers; cMyc; eIF4A; m(6)A mRNA modification; mRNA stability; mTORC1
    DOI:  https://doi.org/10.1016/j.molcel.2021.03.010
  5. Front Immunol. 2021 ;12 637933
    Analysis of m6A-Related Signatures in the Tumor Immune Microenvironment and Identification of Clinical Prognostic Regulators in Adrenocortical Carcinoma.
    Yi Jin, Zhanwang Wang, Dong He, Yuxing Zhu, Xueying Hu, Lian Gong, Mengqing Xiao, Xingyu Chen, Yaxin Cheng, Ke Cao.
      Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with a high rate of mortality and recurrence. N6-methyladenosine methylation (m6A) is the most common modification to affect cancer development, but to date, the potential role of m6A regulators in ACC prognosis is not well understood. In this study, we systematically analyzed 21 m6A regulators in ACC samples from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) database. We identified three m6A modification patterns with different clinical outcomes and discovered a significant relationship between diverse m6A clusters and the tumor immune microenvironment (immune cell types and ESTIMATE algorithm). Additionally, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) revealed that the m6A clusters were strongly associated with immune infiltration in the ACC. Next, to further explore the m6A prognostic signatures in ACC, we implemented Lasso (Least Absolute Shrinkage and Selection Operator) Cox regression to establish an eight-m6A-regulator prognostic model in the TCGA dataset, and the results showed that the model-based high-risk group was closely correlated with poor overall survival (OS) compared with the low-risk group. Subsequently, we validated the key modifications in the GEO datasets and found that high HNRNPA2B1 expression resulted in poor OS and event-free survival (EFS) in ACC. Moreover, to further decipher the molecular mechanisms, we constructed a competing endogenous RNA (ceRNA) network based on HNRNPA2B1, which consists of 12 long noncoding RNAs (lncRNAs) and 1 microRNA (miRNA). In conclusion, our findings indicate the potential role of m6A modification in ACC, providing novel insights into ACC prognosis and guiding effective immunotherapy.
    Keywords:  HNRNPA2B1; M6A; adrenocortical carcinoma; prognostic signatures; tumor immune microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2021.637933
  6. Front Immunol. 2021 ;12 630358
    Emerging Perspectives of RNA N 6-methyladenosine (m6A) Modification on Immunity and Autoimmune Diseases.
    Lipeng Tang, Xingyan Wei, Tong Li, Yi Chen, Zhenhua Dai, Chuanjian Lu, Guangjuan Zheng.
      N6-methyladenosine (m6A) modification, the addition of a methylation decoration at the position of N6 of adenosine, is one of the most prevalent modifications among the over 100 known chemical modifications of RNA. Numerous studies have recently characterized that RNA m6A modification functions as a critical post-transcriptional regulator of gene expression through modulating various aspects of RNA metabolism. In this review, we will illustrate the current perspectives on the biological process of m6A methylation. Then we will further summarize the vital modulatory effects of m6A modification on immunity, viral infection, and autoinflammatory disorders. Recent studies suggest that m6A decoration plays an important role in immunity, viral infection, and autoimmune diseases, thereby providing promising biomarkers and therapeutic targets for viral infection and autoimmune disorders.
    Keywords:  N6-methyladenosine (m6A); adaptive immunity; autoimmune disease; innate immunity; viral infection
    DOI:  https://doi.org/10.3389/fimmu.2021.630358
  7. Oncogene. 2021 Mar 23.
    METTL3-mediated m6A methylation of SPHK2 promotes gastric cancer progression by targeting KLF2.
    Fu-Chun Huo, Zhi-Man Zhu, Wen-Tao Zhu, Qiu-Ying Du, Jia Liang, Jie Mou.
      N6-methyladenosine (m6A) RNA methylation is profoundly involved in epigenetic regulation, especially for carcinogenesis and tumor progression. Mounting evidence suggests that methyltransferase METTL3 regulates malignant behaviors of gastric cancer (GC). However, the clinical significance and biological implication of SPHK2 and its related m6A modification in GC remain unclear. In this study, quantitative real-time PCR (qRT-PCR), western blot and immunohistochemistry were utilized to detect the expression profiles and prognostic significance of SPHK2 in GC. Here, we showed that increased SPHK2 was signified a poor prognosis of GC patients. Phosphorylation and ubiquitination assays were used to investigate the possible mechanisms of SPHK2-mediated KLF2 expression. SPHK2 can promote the phosphorylation of KLF2, which triggers the ubiquitination and degradation of KLF2 protein in GC. Methylated RNA immunoprecipitation (MeRIP) was performed to uncover the m6A modification of SPHK2 mRNA. METTL3 promotes translation of SPHK2 mRNA via an m6A-YTHDF1-dependent manner. Functionally, SPHK2 facilitates GC cell proliferation, migration and invasion by inhibiting KLF2 expression. SPHK2/KLF2 regulates the cell proliferation, migration, and invasion induced by METTL3 in GC. Overall, our findings reveal that METTL3-mediated m6A modification of SPHK2 contributes to GC progression, which extends the understanding of the importance m6A methylation in GC and represents a potential target for GC therapy.
    DOI:  https://doi.org/10.1038/s41388-021-01753-1
  8. Theranostics. 2021 ;11(9): 4298-4315
    N6-methyladenosine-induced circ1662 promotes metastasis of colorectal cancer by accelerating YAP1 nuclear localization.
    Chen Chen, Weitang Yuan, Quanbo Zhou, Bo Shao, Yuying Guo, Weiwei Wang, Shuaixi Yang, Yaxin Guo, Luyang Zhao, Qin Dang, Xiuxiu Yang, Guixian Wang, Qiaozhen Kang, Zhenyu Ji, Jinbo Liu, Zhenqiang Sun.
      Tumor metastasis is the leading cause of death in patients with colorectal cancer (CRC). Circular RNAs (circRNAs) have been shown to be involved in cancer progression. However, the regulatory mechanisms of circRNAs involved in CRC tumor metastasis are currently unknown. Methods: High-throughput sequencing was performed on 6 pairs of CRC and adjacent normal tissues to identify the expression profiles of mRNA and circRNA. circ1662 was assessed by RNA-ISH and IHC of a tissue chip. The function of circ1662 in CRC was evaluated by knocking down or overexpressing circ1662. MeRIP-qPCR, RIP-qPCR, and RNA pull-down were performed to determine the relationship between METTL3, circ1662, and YAP1. Results: A novel circRNA, circ1662, exhibited significantly higher expression in CRC tissues than paired normal tissues. High circ1662 expression was correlated with poor prognosis and tumor depth in patients with CRC. Functionally, circ1662 promoted CRC cell invasion and migration by controlling EMT in vitro and in vivo. Mechanistically, circ1662 directly bound to YAP1 and accelerated its nuclear accumulation to regulate the SMAD3 pathway. Additionally, circ1662 enhanced CRC invasion and migration depending on YAP1 and SMAD3. Interestingly, METTL3 induced circ1662 expression by binding its flanking sequences and installing m6A modifications. Clinically, circ1662 expression strongly correlated with METTL3 and YAP1 protein expression. Moreover, YAP1 expression was negatively correlated with SMAD3 expression. Conclusions: METTL3-induced circ1662 promoted CRC cell invasion and migration by accelerating YAP1 nuclear transport. This result implies that circ1662 is a new prognostic and therapeutic marker for CRC metastasis.
    Keywords:  METTL3; N6-methyladenosine (m6A); YAP1; circ1662; colorectal cancer
    DOI:  https://doi.org/10.7150/thno.51342
  9. Dev Cell. 2021 Mar 16. pii: S1534-5807(21)00203-3. [Epub ahead of print]
    RNA demethylation by FTO stabilizes the FOXJ1 mRNA for proper motile ciliogenesis.
    Hyunjoon Kim, Young-Suk Lee, Seok-Min Kim, Soohyun Jang, Hyunji Choi, Jae-Won Lee, Tae-Don Kim, V Narry Kim.
      Adenosine N6-methylation (m6A) is one of the most pervasive mRNA modifications, and yet the physiological significance of m6A removal (demethylation) remains elusive. Here, we report that the m6A demethylase FTO functions as a conserved regulator of motile ciliogenesis. Mechanistically, FTO demethylates and thereby stabilizes the mRNA that encodes the master ciliary transcription factor FOXJ1. Depletion of Fto in Xenopus laevis embryos caused widespread motile cilia defects, and Foxj1 was identified as one of the major phenocritical targets. In primary human airway epithelium, FTO depletion also led to FOXJ1 mRNA destabilization and a severe loss of ciliated cells with an increase of neighboring goblet cells. Consistently, Fto knockout mice showed strong asthma-like phenotypes upon allergen challenge, a result owing to defective ciliated cells in the airway epithelium. Altogether, our study reveals a conserved role of the FTO-FOXJ1 axis in embryonic and homeostatic motile ciliogenesis.
    Keywords:  FOXJ1; FTO; N6-methyladenosine; RNA modification; airway epithelium; asthma; m6A; motile ciliogenesis
    DOI:  https://doi.org/10.1016/j.devcel.2021.03.006
  10. J Cell Mol Med. 2021 Mar 23.
    METTL3 attenuates proliferative vitreoretinopathy and epithelial-mesenchymal transition of retinal pigment epithelial cells via wnt/β-catenin pathway.
    Xinqi Ma, Chongde Long, Fangyu Wang, Bingsheng Lou, Miner Yuan, Fang Duan, Yao Yang, Jiaqing Li, Xiaobing Qian, Jieting Zeng, Shuibin Lin, Huangxuan Shen, Xiaofeng Lin.
      Proliferative vitreoretinopathy (PVR) is a refractory vitreoretinal fibrosis disease, and epithelial-mesenchymal transition (EMT) of retinal pigment epithelial (RPE) cells is the key pathological mechanism of PVR. However, few studies focused on the role of METTL3, the dominating methyltransferase for m6A RNA modification in PVR pathogenesis. Immunofluorescence staining and qRT-PCR were used to determine the expression of METTL3 in human tissues. Lentiviral transfection was used to stably overexpress and knockdown METTL3 in ARPE-19 cells. MTT assay was employed to study the effects of METTL3 on cell proliferation. The impact of METTL3 on the EMT of ARPE-19 cells was assessed by migratory assay, morphological observation and expression of EMT markers. Intravitreal injection of cells overexpressing METTL3 was used to assess the impact of METTL3 on the establishment of the PVR model. We found that METTL3 expression was less in human PVR membranes than in the normal RPE layers. In ARPE-19 cells, total m6A abundance and the METTL3 expression were down-regulated after EMT. Additionally, METTL3 overexpression inhibited cell proliferation through inducing cell cycle arrest at G0/G1 phase. Furthermore, METTL3 overexpression weakened the capacity of TGFβ1 to trigger EMT by regulating wnt/β -catenin pathway. Oppositely, knockdown of METTL3 facilitated proliferation and EMT of ARPE-19 cells. In vivo, intravitreal injection of METTL3-overexpressing cells delayed the development of PVR compared with injection of control cells. In summary, this study suggested that METTL3 is involved in the PVR process, and METTL3 overexpression inhibits the EMT of ARPE-19 cells in vitro and suppresses the PVR process in vivo.
    Keywords:  METTL3; epithelial-mesenchymal transition; m6A RNA methylation; proliferative vitreoretinopathy; retinal pigment epithelial
    DOI:  https://doi.org/10.1111/jcmm.16476
  11. Nucleic Acids Res. 2021 Mar 21. pii: gkab124. [Epub ahead of print]
    Modeling multi-species RNA modification through multi-task curriculum learning.
    Yuanpeng Xiong, Xuan He, Dan Zhao, Tingzhong Tian, Lixiang Hong, Tao Jiang, Jianyang Zeng.
      N6-methyladenosine (m6A) is the most pervasive modification in eukaryotic mRNAs. Numerous biological processes are regulated by this critical post-transcriptional mark, such as gene expression, RNA stability, RNA structure and translation. Recently, various experimental techniques and computational methods have been developed to characterize the transcriptome-wide landscapes of m6A modification for understanding its underlying mechanisms and functions in mRNA regulation. However, the experimental techniques are generally costly and time-consuming, while the existing computational models are usually designed only for m6A site prediction in a single-species and have significant limitations in accuracy, interpretability and generalizability. Here, we propose a highly interpretable computational framework, called MASS, based on a multi-task curriculum learning strategy to capture m6A features across multiple species simultaneously. Extensive computational experiments demonstrate the superior performances of MASS when compared to the state-of-the-art prediction methods. Furthermore, the contextual sequence features of m6A captured by MASS can be explained by the known critical binding motifs of the related RNA-binding proteins, which also help elucidate the similarity and difference among m6A features across species. In addition, based on the predicted m6A profiles, we further delineate the relationships between m6A and various properties of gene regulation, including gene expression, RNA stability, translation, RNA structure and histone modification. In summary, MASS may serve as a useful tool for characterizing m6A modification and studying its regulatory code. The source code of MASS can be downloaded from https://github.com/mlcb-thu/MASS.
    DOI:  https://doi.org/10.1093/nar/gkab124
  12. J Cell Mol Med. 2021 Mar 21.
    Dysregulation of LINC00470 and METTL3 promotes chemoresistance and suppresses autophagy of chronic myelocytic leukaemia cells.
    Xun Lai, Jia Wei, Xue-Zhong Gu, Xiang-Mei Yao, Di-Si Zhang, Feng Li, Yun-Yan Sun.
      Cytoplasmic lncRNAs have been found to directly interact with target mRNAs and regulate their stability. In this study, we aimed to study the molecular mechanism underlying the function of m6 A as a central regulator in chemoresistance and CML proliferation. In this study, we established three mice groups (control group, ADR-R group and ADR-R + shLINC00470 group). We detected PTEN mRNA expression in the presence of LINC00470 in the mice models, as well as in the KCL22 and K562 cells. LINC00470 was significantly enriched for PTEN mRNA to exhibit a negative regulatory relationship between LINC00470 and PTEN mRNA. However, the alteration of LINC00470 had no effect on the luciferase activity of PTEN promoter, while the half-life of PTEN mRNA was affected. It was further validated that LINC00470 down-regulated PTEN expression by positively regulating the m6A modification of PTEN mRNA via RNA methyltransferase METTL3. Moreover, the relative expression of LC3II, Beclin-1, ATG7 and ATG5 was all decreased in cells treated with LINC00470, and down-regulated PTEN expression was observed in chemo-resistant cells, while the expression of PTEN was rescued by the transfection of shMETTL3 into chemo-resistant cells. Moreover, the knockdown of METTL3 also restored the normal level of PTEN m6 A modification and LINC00470 expression in chemo-resistant cells. In conclusion, our results demonstrated the molecular mechanism underlying the effect of LINC00470 on CML by reducing the PTEN stability via RNA methyltransferase METTL3, thus leading to the inhibition of cell autophagy while promoting chemoresistance in CML.
    Keywords:  AKT; Chronic myelocytic leukaemia; LINC00470; METTL3; PTEN; autophagy; chemoresistance
    DOI:  https://doi.org/10.1111/jcmm.16478
  13. Front Cell Dev Biol. 2021 ;9 642437
    N6-Methyladenosine Induced miR-34a-5p Promotes TNF-α-Induced Nucleus Pulposus Cell Senescence by Targeting SIRT1.
    Hao Zhu, Bao Sun, Liang Zhu, Guoyou Zou, Qiang Shen.
      Low back pain is tightly associated with intervertebral disc degeneration (IVDD) and aberrant nucleus pulposus (NP) is a critical cause. miRNAs N6-methyladenosine (m6A) modification accounts for the TNF-α-induced senescence of NP cells. The aim of this study was to investigate whether m6A modification regulates TNF-α-mediated cell viability, cell cycle arrest, and cell senescence and how it works. The results showed that METTL14 expression positively correlated with m6A and TNF-α expression in HNPCs. The knockdown of METTL14 led to the inhibition of the TNF-α-induced cell senescence. METTL14 overexpression promoted cell senescence. METTL14 regulated the m6A modification of miR-34a-5p and interacted with DGCR8 to process miR-34a-5p. The miR-34a-5p inhibitor inhibited the cell cycle senescence of HNPCs. miR-34a-5p was predicted to interact with the SIRT1 mRNA. SIRT1 overexpression counteracted the miR-34a-5p-promoted cell senescence. METTL14 participates in the TNF-α-induced m6A modification of miR-34a-5p to promote cell senescence in HNPCs and NP cells of IVDD patients. Downregulation of either METTL14 expression or miR-34a-5p leads to the inhibition of cell cycle arrest and senescence. SIRT1 mRNA is an effective binding target of miR-34a-5p, and SIRT1 overexpression mitigates the cell cycle arrest and senescence caused by miR-34a-5p.
    Keywords:  IVDD; N6-methyladenosine; SIRT1; cell senescence; miR-34a-5p
    DOI:  https://doi.org/10.3389/fcell.2021.642437
  14. Mol Carcinog. 2021 Mar 23.
    N6 -Methyladenosine (m6 A) readers are dysregulated in renal cell carcinoma.
    Felix von Hagen, Larissa Gundert, Alexander Strick, Niklas Klümper, Doris Schmidt, Glen Kristiansen, Yuri Tolkach, Marieta Toma, Manuel Ritter, Jörg Ellinger.
      N6 -Methyladenosine (m6 A) is the most common modification of messenger RNA (mRNA) in mammals. It critically influences RNA metabolism and plays an essential role in virtually all types of bioprocesses including gene expression, tissue development, self-renewal and differentiation of stem cells, stress response and circadian clock control. It plays a crucial role in carcinogenesis and could be used as a prognostic and a diagnostic tool and as a target for new anticancer therapies. m6 A modification is dynamically and reversibly regulated by three types of proteins. Methyltransferases, so-called "writers" add a methyl group to the adenosine, which can be removed by demethylases, also called "erasers." m6 A-specific RNA-binding proteins, from here on referred to as "readers," preferentially bind to the m6 A site and mediate biological functions, such as translation, splicing or decay of RNA. In this study, we examined the expression of the six m6 A readers HNRNPA2B1, HNRNPC, YTHDC1 and YTHDF1-3 in clear cell renal carcinoma (ccRCC). We show that on mRNA level the expression of all six m6 A readers is significantly downregulated compared to normal renal tissue and on protein level five out of six readers are dysregulated. Lower levels of some m6 A readers are correlated with advanced stage and grade as well as associated with a shorter overall, progression-free and cancer-specific survival. In summary, we could show that m6 A readers are dysregulated in ccRCC and might therefore act as a tumor marker, could give further information on the individual prognosis and be a target of innovative cancer therapy.
    Keywords:  N6-methyladenosine; YTHDC1; YTHDF1; YTHDF3; renal cell carcinoma
    DOI:  https://doi.org/10.1002/mc.23297
  15. Blood. 2021 Mar 24. pii: blood.2020009676. [Epub ahead of print]
    YBX1 is required for maintaining myeloid leukemia cell survival by regulating BCL2 stability in an m6A-dependent manner.
    Mengdie Feng, Xueqin Xie, Guoqiang Han, Tiantian Zhang, Yashu Li, Yicun Li, Rong Yin, Qifan Wang, Tong Zhang, Peipei Wang, Jin Hu, Ying Cheng, Zhuying Gao, Jing Wang, Jiwei Chang, Manman Cui, Kexin Gao, Jihua Chai, Weidong Liu, Chengli Guo, Shaoguang Li, Lingbo Liu, Fuling Zhou, Jianjun Chen, Haojian Zhang.
      RNA-binding proteins (RBPs) are critical regulators of transcription and translation that are often dysregulated in cancer. Although RBPs are increasingly appreciated as being important for normal hematopoiesis and for hematological malignancies as oncogenes or tumor suppressors, essential RBPs for leukemia maintenance and survival remain elusive. Here we show that YBX1 is specifically required for maintaining myeloid leukemia cell survival in an m6A-dependent manner. We found that expression of YBX1 is significantly upregulated in myeloid leukemia cells, and deletion of YBX1 dramatically induces apoptosis, promotes differentiation, coupled with reduced proliferation and impaired leukemic capacity of primary human and mouse acute myeloid leukemia (AML) cells in vitro and in vivo. Loss of YBX1 does not obviously affect normal hematopoiesis. Mechanistically, YBX1 interacts with IGF2BPs and stabilizes m6A-tagged RNA. Moreover, YBX1 deficiency dysregulates the expression of apoptosis-related genes, and promotes mRNA decay of MYC and BCL2 in an m6A-dependent manner, which contributes to the defective survival due to YBX1 deletion. Thus, our findings uncover a selective and critical role of YBX1 in maintaining myeloid leukemia survival that might provide a rationale for the therapeutic targeting of YBX1 in myeloid leukemia.
    DOI:  https://doi.org/10.1182/blood.2020009676
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