bims-rimeca Biomed News
on RNA methylation in cancer
Issue of 2022–02–06
fiveteen papers selected by
Sk Ramiz Islam, Saha Institute of Nuclear Physics
  1. m6A Methyltransferase METTL3 Promotes the Progression of Primary Acral Melanoma via Mediating TXNDC5 Methylation.
  2. METTL3 promotes intrahepatic cholangiocarcinoma progression by regulating IFIT2 expression in an m6A-YTHDF2-dependent manner.
  3. YTHDF3 modulates hematopoietic stem cells by recognizing RNA m6A modification on Ccnd1.
  4. M6A demethylase FTO-mediated downregulation of DACT1 mRNA stability promotes Wnt signaling to facilitate osteosarcoma progression.
  5. METTL3 Contributes to Osteosarcoma Progression by Increasing DANCR mRNA Stability via m6A Modification.
  6. Demethylase ALKBH5 suppresses invasion of gastric cancer via PKMYT1 m6A modification.
  7. The m6A reading protein YTHDF3 potentiates tumorigenicity of cancer stem-like cells in ocular melanoma through facilitating CTNNB1 translation.
  8. Downregulation of the FTO m6A RNA demethylase promotes EMT-mediated progression of epithelial tumors and sensitivity to Wnt inhibitors.
  9. Potential applications of N6 -methyladenosine modification in the prognosis and treatment of cancers via modulating apoptosis, autophagy, and ferroptosis.
  10. IGF2BP2 Regulates MALAT1 by Serving as an N6-Methyladenosine Reader to Promote NSCLC Proliferation.
  11. m6A modifications regulate intestinal immunity and rotavirus infection.
  12. The cancer-testis lncRNA lnc-CTHCC promotes hepatocellular carcinogenesis by binding hnRNP K and activating YAP1 transcription.
  13. RNA N6-Methyladenosine Regulators Contribute to Tumor Immune Microenvironment and Have Clinical Prognostic Impact in Breast Cancer.
  14. N6-Methyladenosine-Related LncRNAs Are Potential Remodeling Indicators in the Tumor Microenvironment and Prognostic Markers in Osteosarcoma.
  15. N6-methyladenosine-dependent modification of circGARS acts as a new player that promotes SLE progression through the NF-κB/A20 axis.
  1. Front Oncol. 2021 ;11 770325
    m6A Methyltransferase METTL3 Promotes the Progression of Primary Acral Melanoma via Mediating TXNDC5 Methylation.
    Zhanghui Yue, Meng Cao, Anlan Hong, Qian Zhang, Guoqiang Zhang, Zhibin Jin, Liang Zhao, Qiang Wang, Fang Fang, Yan Wang, Jianfang Sun.
      m6A modification is one of the most important post-transcriptional modifications in RNA and plays an important role in promoting translation or decay of RNAs. The role of m6A modifications has been highlighted by increasing evidence in various cancers, which, however, is rarely explored in acral melanoma. Here, we demonstrated that m6A level was highly elevated in acral melanoma tissues, along with the expression of METTL3, one of the most important m6A methyltransferase. Besides, higher expression of METTL3 messenger RNA (mRNA) correlated with a higher stage in primary acral melanoma patients. Knockdown of METTL3 decreased global m6A level in melanoma cells. Furthermore, METTL3 knockdown suppressed the proliferation, migration, and invasion of melanoma cells. In METTL3 knockdown xenograft mouse models, we observed decreased volumes and weights of melanoma tissues. Mechanistically, we found that METTL3 regulates certain m6A-methylated transcripts, thioredoxin domain containing protein 5 (TXNDC5), with the confirmation of RNA-seq, MeRIP-seq, and Western blot. These data suggest that METTL3 may play a key role in the progression of acral melanoma, and targeting the m6A dependent-METTL3 signaling pathway may serve as a promising therapeutic strategy for management of patients of acral melanomas.
    Keywords:  Mettl3 (methyltransferase like 3); TXNDC5; m6A (N6-methyladenose); melanoma; progression
    DOI:  https://doi.org/10.3389/fonc.2021.770325
  2. Oncogene. 2022 Jan 29.
    METTL3 promotes intrahepatic cholangiocarcinoma progression by regulating IFIT2 expression in an m6A-YTHDF2-dependent manner.
    Qiong-Cong Xu, Yi-Chih Tien, Yin-Hao Shi, Siyun Chen, Ying-Qin Zhu, Xi-Tai Huang, Chen-Song Huang, Wei Zhao, Xiao-Yu Yin.
      N6-methyladenosine (m6A) RNA methylation has recently been found involving in regulatory mechanism of the tumor progression. Our aim was to explore the biological function and clinical significance of the m6A methyltransferase METTL3 in intrahepatic cholangiocarcinoma (ICC). In this study, we revealed that METTL3 was upregulated and predicted poor prognosis of patients with ICC. Multivariate regression analysis demonstrated that METTL3 expression was an independent predictor for overall survival in patients with ICC. Moreover, METTL3 knockdown inhibited ICC progression, while METTL3 overexpression showed the opposite effect. METTL3 inhibitor STM2457 also showed anti-tumor effect in ICC. Mechanistically, METTL3 transcription was driven by H3K4me3 activation. Upregulation of METTL3 mediated m6A modification of IFIT2 mRNA and accelerated IFIT2 mRNA decay in a YTHDF2-dependent manner, which promoted the development of ICC and lead to poorer prognosis. In summary, our findings revealed that H3K4me3 activation-driven METTL3 transcription promotes ICC progression by YTHDF2-mediated IFIT2 mRNA degradation, suggesting that METTL3 may serve as a potential target for human ICC therapy.
    DOI:  https://doi.org/10.1038/s41388-022-02185-1
  3. Haematologica. 2022 Feb 03.
    YTHDF3 modulates hematopoietic stem cells by recognizing RNA m6A modification on Ccnd1.
    Xiaofei Zhang, Tingting Cong, Lei Wei, Bixi Zhong, Xiaowo Wang, Jin Sun, Shuxia Wang, Meng Michelle Xu, Ping Zhu, Hong Jiang, Jianwei Wang.
      Hematopoietic stem cells (HSCs) build up the blood system throughout lifespan. N6-methyladenosine (m6A), the most prevalent RNA modification, modulates gene expression via the processes of "writing" and "reading". Recent studies showed that m6A "writer" genes (Mettl3 and Mettl14) play an essential role in HSCs. However, which reader deciphers the m6A modification to modulate HSCs remains unknown. In this study, we observed that dysfunction of Ythdf3 and Ccnd1 severely impaired the reconstitution capacity of HSCs, which phenocopies Mettl3 deficient HSCs. Dysfunction of Ythdf3 and Mettl3 results in the translational defect of Ccnd1. Ythdf3 and Mettl3 regulates HSCs by transmitting m6A RNA methylation on the 5'UTR of Ccnd1. Enforced Ccnd1 completely rescues the defect of Ythdf3-/- HSCs and partially rescues Mettl3-compromised HSCs. Taken together, this study for the first time identified that Ccnd1 is the target of METTL3 and YTHDF3 to transmit m6A RNA methylation signal to regulate HSCs reconstitution capacity.
    DOI:  https://doi.org/10.3324/haematol.2021.279739
  4. Oncogene. 2022 Feb 04.
    M6A demethylase FTO-mediated downregulation of DACT1 mRNA stability promotes Wnt signaling to facilitate osteosarcoma progression.
    Dongming Lv, Shirong Ding, Li Zhong, Jian Tu, Hongbo Li, Hao Yao, Yutong Zou, Ziliang Zeng, Yan Liao, Xuesi Wan, Lili Wen, Xianbiao Xie.
      Despite advances in clinical diagnosis and treatment, the prognosis of patients with osteosarcoma (OS) remains poor, and the treatment efficacy has plateaued. Therefore, it is important to identify new therapeutic targets for OS. N6-methyladenosine (m6A) modification has been reported to participate in tumor malignancy. In this study, functional screening showed that the m6A demethylase FTO could be a candidate therapeutic target for OS. Upregulated FTO in OS could predict a poorer prognosis. FTO promoted the growth and metastasis of OS in vitro and in vivo. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA sequencing (RNA-seq) were performed to identify DACT1 as a potential target of FTO. In vitro assays demonstrated that FTO could reduce the mRNA stability of DACT1 via m6A demethylation, which decreased DACT1 expression and further activated the Wnt signaling pathway. The oncogenic effect of FTO on OS was dependent on DACT1. In addition, the m6A reader IGF2BP1 was validated to participate in the regulation of DACT1. Entacapone, a conventional drug for Parkinson's disease, was confirmed to suppress OS via m6A-mediated regulation through the FTO/DACT1 axis. Our findings demonstrate that FTO may be a novel therapeutic target and that entacapone has preclinical value to be repurposed for OS.
    DOI:  https://doi.org/10.1038/s41388-022-02214-z
  5. Front Cell Dev Biol. 2021 ;9 784719
    METTL3 Contributes to Osteosarcoma Progression by Increasing DANCR mRNA Stability via m6A Modification.
    Xinying Zhou, Yang Yang, Yuejun Li, Guojun Liang, Dawei Kang, Bing Zhou, Qingchu Li.
      Background: Osteosarcoma (OS) is the most prevalent bone cancer among children and adolescents, with relatively high mortality rates. RNA N6-methyladenosine (m6A) is the most common human mRNA modification with diverse functions in a variety of biological processes. Previous studies indicated that methyltransferase-like 3 (METTL3), the first methyltransferase to be identified, acted as an oncogene or tumor suppressor in multiple human cancers. However, its functions and underlying mechanisms in OS progression remain unclear; therefore, we explored these processes. Methods: We used real-time quantitative PCR (RT-qPCR) and Western blot assays to explore METTL3 expression in OS tumor tissues and five OS cell lines to assess its clinical significance. To further examine the functional role of METTL3 during OS progression, CCK-8 analyses, transwell assays, and xenograft model studies were conducted after silencing METTL3. Additionally, underlying mechanisms were also explored using RIP-seq and RIP-qPCR approaches. Results: METTL3 was upregulated in OS tumor tissues and cell lines and was associated with a worse prognosis. Moreover, METTL3 silencing suppressed OS cell proliferation, migration, and invasion. Also, in vivo METTL3 oncogenic functions were confirmed in the xenograft model. Comprehensive mechanistic analyses identified long non-coding RNA (lncRNA) DANCR as a potential target of METTL3, as indicated by reduced DANCR levels after METTL3 silencing. Also, lncRNA DANCR knockdown repressed OS cell proliferation, migration, and invasion. Furthermore, both METTL3 and lncRNA DANCR silencing significantly suppressed OS growth and metastasis. Finally, we hypothesized that METTL3 regulated DANCR expression via m6A modification-mediated DANCR mRNA stability. Conclusion: METTL3 contributes to OS progression by increasing DANCR mRNA stability via m6A modification, meaning that METTL3 may be a promising therapeutic target for OS treatment.
    Keywords:  METTL3; lncRNA DANCR; m6A modification; mRNA stability; osteosarcoma
    DOI:  https://doi.org/10.3389/fcell.2021.784719
  6. Mol Cancer. 2022 Feb 03. 21(1): 34
    Demethylase ALKBH5 suppresses invasion of gastric cancer via PKMYT1 m6A modification.
    Yiyang Hu, Chunli Gong, Zhibin Li, Jiao Liu, Yang Chen, Yu Huang, Qiang Luo, Sumin Wang, Yu Hou, Shiming Yang, Yufeng Xiao.
       BACKGROUND: Gastric cancer (GC) is one of the most pernicious tumors that seriously harm human healthcare. GC metastasis is one of the prime cause of failed cancer treatment, but correlation between N6-methyladenosine (m6A) and GC metastasis was less reported.
    METHODS: Methylated RNA immunoprecipitation sequencing (MeRIP-seq) of GC tissues was conducted. Quantitative real-time PCR (qRT-PCR), western blotting and immunohistochemistry (IHC) were taken to determine the expression of ALKBH5 in GC tissues and cell lines. RNA-seq together with MeRIP-qRT-PCR was used to screen the target gene of ALKBH5. RNA pulldown, mass spectrometry and RNA immunoprecipitation (RIP) were used to search the "reader" protein of target gene. The mechanism was also validated via a tail vein injection method for lung metastasis model.
    RESULTS: Decreased expression of ALKBH5 was detected in GC samples, and it was correlated with clinical tumor distal metastasis and lymph node metastasis. ALKBH5 interference promoted metastasis of GC cells and this effect was closely related to the demethylase activity of ALKBH5. PKMYT1, as a downstream target of ALKBH5, promoted invasion and migration in GC. Caused by ALKBH5 knockdown or its demethylase activity mutation, upregulated expression of PKMYT1 indicated that ALKBH5 modulates expression of PKMYT1 in an m6A-dependent manner. IGF2BP3 helped stabilize the mRNA stability of PKMYT1 via its m6A modification site.
    CONCLUSIONS: This study established an ALKBH5-PKMYT1-IGF2BP3 regulation system in metastasis, representing a new therapeutic target for GC metastasis.
    Keywords:  ALKBH5; Demethylase activity; Gastric cancer; Invasion; Metastasis; PKMYT1
    DOI:  https://doi.org/10.1186/s12943-022-01522-y
  7. Oncogene. 2022 Feb 03.
    The m6A reading protein YTHDF3 potentiates tumorigenicity of cancer stem-like cells in ocular melanoma through facilitating CTNNB1 translation.
    Yangfan Xu, Xiaoyu He, Shanzheng Wang, Baofa Sun, Ruobing Jia, Peiwei Chai, Fang Li, Ying Yang, Shengfang Ge, Renbing Jia, Yun-Gui Yang, Xianqun Fan.
      N6-methyladenosine (m6A) is the most universal internal RNA modification on messenger RNAs and regulates the fate and functions of m6A-modified transcripts through m6A-specific binding proteins. Nevertheless, the functional role and potential mechanism of the m6A reading proteins in ocular melanoma tumorigenicity, especially cancer stem-like cell (CSC) properties, remain to be elucidated. Herein, we demonstrated that the m6A reading protein YTHDF3 promotes the translation of the target transcript CTNNB1, contributing to ocular melanoma propagation and migration through m6A methylation. YTHDF3 is highly expressed in ocular melanoma stem-like cells and abundantly enriched in ocular melanoma tissues, which is related to poor clinical prognosis. Moreover, YTHDF3 is required for the maintenance of CSC properties and tumor initiation capacity in ocular melanoma both in vitro and in vivo. Ocular melanoma cells with targeted YTHDF3 knockdown exhibited inhibitory tumor proliferation and migration abilities. Transcriptome-wide mapping of m6A peaks and YTHDF3 binding peaks on mRNAs revealed a key target gene candidate, CTNNB1. Mechanistically, YTHDF3 enhances CTNNB1 translation through recognizing and binding the m6A peaks on CTNNB1 mRNA.
    DOI:  https://doi.org/10.1038/s41388-021-02146-0
  8. Nat Cancer. 2021 Jun;2(6): 611-628
    Downregulation of the FTO m6A RNA demethylase promotes EMT-mediated progression of epithelial tumors and sensitivity to Wnt inhibitors.
    Jana Jeschke, Evelyne Collignon, Clémence Al Wardi, Mohammad Krayem, Martin Bizet, Yan Jia, Soizic Garaud, Zéna Wimana, Emilie Calonne, Bouchra Hassabi, Renato Morandini, Rachel Deplus, Pascale Putmans, Gaurav Dube, Nitesh Kumar Singh, Alexander Koch, Kateryna Shostak, Lara Rizzotto, Robert L Ross, Christine Desmedt, Yacine Bareche, Françoise Rothé, Jacqueline Lehmann-Che, Martine Duterque-Coquillaud, Xavier Leroy, Gerben Menschaert, Luis Teixeira, Mingzhou Guo, Patrick A Limbach, Pierre Close, Alain Chariot, Eleonora Leucci, Ghanem Ghanem, Bi-Feng Yuan, Karen Willard-Gallo, Christos Sotiriou, Jean-Christophe Marine, François Fuks.
      Post-transcriptional modifications of RNA constitute an emerging regulatory layer of gene expression. The demethylase fat mass- and obesity-associated protein (FTO), an eraser of N6-methyladenosine (m6A), has been shown to play a role in cancer, but its contribution to tumor progression and the underlying mechanisms remain unclear. Here, we report widespread FTO downregulation in epithelial cancers associated with increased invasion, metastasis and worse clinical outcome. Both in vitro and in vivo, FTO silencing promotes cancer growth, cell motility and invasion. In human-derived tumor xenografts (PDXs), FTO pharmacological inhibition favors tumorigenesis. Mechanistically, we demonstrate that FTO depletion elicits an epithelial-to-mesenchymal transition (EMT) program through increased m6A and altered 3'-end processing of key mRNAs along the Wnt signaling cascade. Accordingly, FTO knockdown acts via EMT to sensitize mouse xenografts to Wnt inhibition. We thus identify FTO as a key regulator, across epithelial cancers, of Wnt-triggered EMT and tumor progression and reveal a therapeutically exploitable vulnerability of FTO-low tumors.
    DOI:  https://doi.org/10.1038/s43018-021-00223-7
  9. Wiley Interdiscip Rev RNA. 2022 Feb 03. e1719
    Potential applications of N6 -methyladenosine modification in the prognosis and treatment of cancers via modulating apoptosis, autophagy, and ferroptosis.
    Yuan Zhi, Shanshan Zhang, Moxin Zi, Yian Wang, Yuhang Liu, Mi Zhang, Lei Shi, Qijia Yan, Zhaoyang Zeng, Wei Xiong, Keqian Zhi, Zhaojian Gong.
      N6 -methyladenosine (m6 A) is one of the most abundant modifications determining the fate of RNA. Currently, m6 A modification is tightly connected with tumorigenesis and presents novel promise in clinical applications. Regulated cell death (RCD) is a programmed mechanism that plays a complicated role in malignant transition. Regarding the main forms of RCD, aberrant levels of m6 A modification have been detected during the progression of apoptosis, autophagy, ferroptosis, necroptosis, and pyroptosis in several diseases. However, few reviews have elucidated the correlation between m6 A-modified RCD and carcinogenesis. In this review, we summarize the regulators of m6 A methylation and their functions in carcinogenesis through an overview of m6 A-modified RCD. Additionally, we assume the potential role of m6 A modification regulators as novel biomarkers for chemotherapies and precision medicine. Furthermore, we review the controversies and conflicts in m6 A explorations and predict future orientations of m6 A-modified RCD for clinical applications. This article is categorized under: Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs.
    Keywords:  autophagy; carcinogenesis; ferroptosis; m6A modification; necroptosis; regulated cell death
    DOI:  https://doi.org/10.1002/wrna.1719
  10. Front Mol Biosci. 2021 ;8 780089
    IGF2BP2 Regulates MALAT1 by Serving as an N6-Methyladenosine Reader to Promote NSCLC Proliferation.
    Le Han, Guangyan Lei, Zhenghong Chen, Yili Zhang, Chen Huang, Wenjuan Chen.
      Insulin-like growth factor 2 (IGF2) mRNA-binding protein 2 (IGF2BP2) is an important posttranscriptional regulatory for stability and m6A modification. Here, we investigated the role of IGF2BP2 in non-small-cell lung cancer (NSCLC) proliferation. TCGA database was used to predict the expression and clinical significance of IGF2BP2 in normal and NSCLC samples. The expression of IGF2BP2 was further validated in NSCLC samples from surgery. Then we performed the functional study in NSCLC cell lines through overexpressing and knocking down IGF2BP2 in NSCLC cell lines in vitro and in vivo. The mechanism of interaction between IGF2BP2 and lncRNA metastasis associated lung adenocarcinoma transcript 1 (MALAT1) in NSCLC proliferation was determined by RIP assay. We demonstrated that IGF2BP2 is highly expressed in NSCLC and positively associated with poor overall survival (OS) and disease-free survival (DFS). We identified that lncRNA MALAT1 is a target of IGF2BP2 in NSCLC. IGF2BP2 promotes MALAT1 stability in an m6A-dependent mechanism, thus promoting its downstream target autophagy-related (ATG)12 expression and NSCLC proliferation.
    Keywords:  ATG12; IGF2BP2; M6A; MALAT1; NSCLC
    DOI:  https://doi.org/10.3389/fmolb.2021.780089
  11. Elife. 2022 Jan 31. pii: e73628. [Epub ahead of print]11
    m6A modifications regulate intestinal immunity and rotavirus infection.
    Anmin Wang, Wanyiin Tao, Jiyu Tong, Juanzi Gao, Jinghao Wang, Gaopeng Hou, Chen Qian, Guorong Zhang, Runzhi Li, Decai Wang, Xingxing Ren, Kaiguang Zhang, Siyuan Ding, Richard A Flavell, Huabing Li, Wen Pan, Shu Zhu.
      N6-methyladenosine (m6A) is an abundant mRNA modification and affects many biological processes. However, how m6A levels are regulated during physiological or pathological processes such as virus infections, and the in vivo function of m6A in the intestinal immune defense against virus infections are largely unknown. Here, we uncover a novel antiviral function of m6A modification during rotavirus (RV) infection in small bowel intestinal epithelial cells (IECs). We found that rotavirus infection induced global m6A modifications on mRNA transcripts by down-regulating the m6a eraser ALKBH5. Mice lacking the m6A writer enzymes METTL3 in IECs (Mettl3ΔIEC) were resistant to RV infection and showed increased expression of interferons (IFNs) and IFN-stimulated genes (ISGs). Using RNA-sequencing and m6A RNA immuno-precipitation (RIP)-sequencing, we identified IRF7, a master regulator of IFN responses, as one of the primary m6A targets during virus infection. In the absence of METTL3, IECs showed increased Irf7 mRNA stability and enhanced type I and III IFN expression. Deficiency in IRF7 attenuated the elevated expression of IFNs and ISGs and restored susceptibility to RV infection in Mettl3ΔIEC mice. Moreover, the global m6A modification on mRNA transcripts declined with age in mice, with a significant drop from 2 weeks to 3 weeks post birth, which likely has broad implications for the development of intestinal immune system against enteric viruses early in life. Collectively, we demonstrated a novel host m6A-IRF7-IFN antiviral signaling cascade that restricts rotavirus infection in vivo.
    Keywords:  immunology; infectious disease; inflammation; microbiology; mouse; viruses
    DOI:  https://doi.org/10.7554/eLife.73628
  12. Nat Cancer. 2022 Jan 10.
    The cancer-testis lncRNA lnc-CTHCC promotes hepatocellular carcinogenesis by binding hnRNP K and activating YAP1 transcription.
    Anliang Xia, Wenwen Yuan, Qiang Wang, Jianbo Xu, Yayun Gu, Liansheng Zhang, Chen Chen, Zhangding Wang, Di Wu, Qifeng He, Weiwei Yu, Fei Wang, Cailin Xue, Yan Zhang, Guojian Bao, Xuewen Tao, Siyuan Liu, Shouyu Wang, Zhibin Hu, Beicheng Sun.
      Cancer-testis (CT) genes participate in the initiation and progression of cancer, but the role of CT-associated long non-coding RNAs (CT-lncRNAs) in hepatocellular carcinoma (HCC) is still elusive. Here, we discovered a conserved CT-lncRNA, named lnc-CTHCC, which was highly expressed in the testes and HCC. A lnc-CTHCC-knockout (KO) mouse model further confirmed that the global loss of lnc-CTHCC inhibited the occurrence and development of HCC. In vitro and in vivo assays also showed that lnc-CTHCC promoted HCC growth and metastasis. Mechanistically, lnc-CTHCC bound to heterogeneous nuclear ribonucleoprotein K (hnRNP K), which was recruited to the YAP1 promoter for its activation. Additionally, the N6-methyladenosine (m6A) modification was mediated by N6-adenosine-methyltransferase 70-kDa subunit (METTL3) and recognized by insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1)/IGF2BP3, which maintained lnc-CTHCC stability and increased its expression in HCC. Together, our results show that lnc-CTHCC directly binds to hnRNP K and promotes hepatocellular carcinogenesis and progression by activating YAP1 transcription, suggesting that lnc-CTHCC is a potential biomarker and therapeutic target of HCC.
    DOI:  https://doi.org/10.1038/s43018-021-00315-4
  13. Front Genet. 2021 ;12 650499
    RNA N6-Methyladenosine Regulators Contribute to Tumor Immune Microenvironment and Have Clinical Prognostic Impact in Breast Cancer.
    Lan-Xin Mu, You-Cheng Shao, Lei Wei, Fang-Fang Chen, Jing-Wei Zhang.
      Purpose: This study aims to reveal the relationship between RNA N6-methyladenosine (m6A) regulators and tumor immune microenvironment (TME) in breast cancer, and to establish a risk model for predicting the occurrence and development of tumors. Patients and methods: In the present study, we respectively downloaded the transcriptome dataset of breast cancer from Gene Expression Omnibus (GEO) database and The Cancer Genome Atlas (TCGA) database to analyze the mutation characteristics of m6A regulators and their expression profile in different clinicopathological groups. Then we used the weighted correlation network analysis (WGCNA), the least absolute shrinkage and selection operator (LASSO), and cox regression to construct a risk prediction model based on m6A-associated hub genes. In addition, Immune infiltration analysis and gene set enrichment analysis (GSEA) was used to evaluate the immune cell context and the enriched gene sets among the subgroups. Results: Compared with adjacent normal tissue, differentially expressed 24 m6A regulators were identified in breast cancer. According to the expression features of m6A regulators above, we established two subgroups of breast cancer, which were also surprisingly distinguished by the feature of the immune microenvironment. The Model based on modification patterns of m6A regulators could predict the patient's T stage and evaluate their prognosis. Besides, the low m6aRiskscore group presents an immune-activated phenotype as well as a lower tumor mutation load, and its 5-years survival rate was 90.5%, while that of the high m6ariskscore group was only 74.1%. Finally, the cohort confirmed that age (p < 0.001) and m6aRiskscore (p < 0.001) are both risk factors for breast cancer in the multivariate regression. Conclusion: The m6A regulators play an important role in the regulation of breast tumor immune microenvironment and is helpful to provide guidance for clinical immunotherapy.
    Keywords:  breast cancer; m6a; molecular subtype; prognosis; risk model; tumor microenvironment
    DOI:  https://doi.org/10.3389/fgene.2021.650499
  14. Front Immunol. 2021 ;12 806189
    N6-Methyladenosine-Related LncRNAs Are Potential Remodeling Indicators in the Tumor Microenvironment and Prognostic Markers in Osteosarcoma.
    Zhongguang Wu, Xiaobo Zhang, Dongjie Chen, Zian Li, Xin Wu, Jianlong Wang, Youwen Deng.
      N6-Adenosine methylation, yielding N6-methyladenosine (m6A), is a reversible epigenetic modification found in messenger RNAs and long non-coding RNAs (lncRNAs), which affects the fate of modified RNA molecules and is essential for the development and differentiation of immune cells in the tumor microenvironment (TME). Osteosarcoma (OS) is the most common primary bone tumor in children and adolescents, and is characterized by high mortality. Currently, the possible role of m6A modifications in the prognosis of OS is unclear. In the present study, we investigated the correlation between m6A-related lncRNA expression and the clinical outcomes of OS patients via a comprehensive analysis. Clinical and workflow-type data were obtained from the Genotype-Tissue Expression Program and The Cancer Genome Atlas. We examined the relationship between m6A modifications and lncRNA expression, conducted Kyoto Encyclopedia of Genes analysis and also gene set enrichment analysis (GSEA), implemented survival analysis to investigate the association of clinical survival data with the expression of m6A-related lncRNAs, and utilized Lasso regression to model the prognosis of OS. Furthermore, we performed immune correlation analysis and TME differential analysis to investigate the infiltration levels of immune cells and their relationship with clinical prognosis. LncRNA expression and m6A levels were closely associated in co-expression analysis. The expression of m6A-related lncRNAs was quite low in tumor tissues; this appeared to be a predicting factor of OS in a prognostic model, independent of other clinical features. The NOD-like receptor signaling pathway was the most significantly enriched pathway in GSEA. In tumor tissues, SPAG4 was overexpressed while ZBTB32 and DEPTOR were downregulated. Tissues in cluster 2 were highly infiltrated by plasma cells. Cluster 2 presented higher ESTIMATE scores and stromal scores, showing a lower tumor cell purity in the TME. In conclusion, m6A-related lncRNA expression is strongly associated with the occurrence and development of OS, and can be used to as a prognostic factor of OS. Moreover, m6A-related lncRNAs and infiltrating immune cells in the TME could serve as new therapeutic targets and prognostic biomarkers for OS.
    Keywords:  N6-methyladenosine (m6A); epigenetic; long non-coding RNAs (lncRNAs); osteosarcoma; plasma cell; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2021.806189
  15. Arthritis Res Ther. 2022 Feb 04. 24(1): 37
    N6-methyladenosine-dependent modification of circGARS acts as a new player that promotes SLE progression through the NF-κB/A20 axis.
    Xingwang Zhao, Rui Dong, Longlong Zhang, Junkai Guo, Ying Shi, Lan Ge, Juan Wang, Zhiqiang Song, Bing Ni, Yi You.
       BACKGROUND: Certain circRNAs could be used as biomarkers to determine the risk of development and/or severity of systemic lupus erythematosus, and their new function in the regulation of gene expression has motivated us to investigate their role in SLE METHODS: Experimental methods including qRT-PCR, RNA immunoprecipitation (RIP), pulldown, dual luciferase reporter assay, RNA interference and cell transfection, RNA fluorescence in situ hybridization, western blotting, and mass spectrometry were used to assessed circGARS (hsa_circRNA_0009000) for immune functions and defined mechanisms by which circGARS promotes the progression in SLE.
    RESULTS: Our results demonstrated that the levels of circGARS was remarkably upregulated in SLE and correlated with clinicopathological features. CircGARS directly combined with microRNA-19a (miR-19a). Functionally, circGARS downregulated the expression of TNFAIP3 (A20, tumor necrosis factor alpha-induced protein 3) to mediate the activation of immune responses that were regulated by the nuclear factor-κB (NF-κB) pathway as a negative feedback mechanism. In addition, miR-19a regulated A20 (TNFAIP3) degradation by downregulating the expression of YTH N6-methyladenosine RNA-binding protein 2 (YTHDF2).
    CONCLUSIONS: The circGARS sponges miR-19a to regulate YTHDF2 expression to promote SLE progression through the A20/NF-κB axis and may act as an independent biomarker to help the treatment of SLE patients.
    Keywords:  A20; Systemic lupus erythematosus; YTHDF2; circGARS; m6A; miR-19a
    DOI:  https://doi.org/10.1186/s13075-022-02732-x
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