bims-rimeca Biomed News
on RNA methylation in cancer
Issue of 2021–11–21
eleven papers selected by
Sk Ramiz Islam, Saha Institute of Nuclear Physics
  1. An integrated model of FTO and METTL3 expression that predicts prognosis in lung squamous cell carcinoma patients.
  2. METTL3-mediated N6-methyladenosine modification of DUSP5 mRNA promotes gallbladder-cancer progression.
  3. RNA m6A methylation regulators in ovarian cancer.
  4. FTO demethylates YAP mRNA promoting oral squamous cell carcinoma tumorigenesis.
  5. Demethyltransferase FTO alpha-ketoglutarate dependent dioxygenase (FTO) regulates the proliferation, migration, invasion and tumor growth of prostate cancer by modulating the expression of melanocortin 4 receptor (MC4R).
  6. METTL3-Dependent Glycolysis Regulates Dental Pulp Stem Cell Differentiation.
  7. The RNA Methyltransferase METTL3 Promotes Endothelial Progenitor Cell Angiogenesis in Mandibular Distraction Osteogenesis via the PI3K/AKT Pathway.
  8. ADSCs enhance VEGFR3-mediated lymphangiogenesis via METTL3-mediated VEGF-C m6A modification to improve wound healing of diabetic foot ulcers.
  9. m(6)A demethylase ALKBH5 inhibits cell proliferation and the metastasis of colorectal cancer by regulating the FOXO3/miR-21/SPRY2 axis.
  10. Comprehensive of N1-Methyladenosine Modifications Patterns and Immunological Characteristics in Ovarian Cancer.
  11. Balancing of mitochondrial translation through METTL8-mediated m3C modification of mitochondrial tRNAs.
  1. Ann Transl Med. 2021 Oct;9(20): 1523
    An integrated model of FTO and METTL3 expression that predicts prognosis in lung squamous cell carcinoma patients.
    Kun Zhang, Zhaojie Han, Hongmei Zhao, Siyao Liu, Fuchun Zeng.
       Background: Lung squamous cell carcinoma (LUSC) approximately accounts for a third of lung cancers. However, the role of N6-methyladenosine (m6A) in LUSC remains largely unknown according to previous studies.
    Methods: In this study, we investigated the mutations, copy number variants (CNVs), expression of 20 m6A RNA methylation regulators, and clinical data from The Cancer Genome Atlas-LUSC (TCGA-LUSC). These data were used for the training cohort of screening potential biomarkers. The prognostic model of m6A RNA methylation regulators was constructed. A receiver operating characteristic (ROC) analysis was undertaken to determine the area under the curves (AUCs) (for 3- and 5-year survival) for the model. Additionally, the accuracy of the two-gene model was confirmed with external data verifications. Combined two-gene model and clinincal information were performed to construct a nomogram to predict patient's prognostic risk assessment.
    Results: Fat mass- and obesity-associated protein (FTO) and methyltransferase-like 3 (METTL3) were identified as potential prognostic biomarkers to evaluate benign and malignant tumors and prognosticate. The following prognostic model of m6A RNA methylation regulators was constructed: risk score = 0.162 × FTO - 0.069 × METTL3. Patients in low-risk group [median overall survival (mOS), 43.4 months] had longer survival than those with high-risk (mOS, 67.3 months) with P=0.0023. The smoking grade and risk score could be independent prognostic factors (P=0.00098 and P=0.0014, respectively). Ultimately, a nomogram was developed to assist clinicians to predict clinical outcomes.
    Conclusions: FTO and METTL3 are potential prognostic biomarkers of LUSC. The two-gene model's use of prognostic risk scores may provide guidance in the selection of therapeutic strategies.
    Keywords:  Fat mass- and obesity-associated protein (FTO); N6-methyladenosine (m6A); biomarkers; lung squamous cell carcinoma (LUSC); methyltransferase-like 3 (METTL3)
    DOI:  https://doi.org/10.21037/atm-21-4470
  2. Cancer Gene Ther. 2021 Nov 19.
    METTL3-mediated N6-methyladenosine modification of DUSP5 mRNA promotes gallbladder-cancer progression.
    Hua-Dong Chen, Fuxi Li, Siyun Chen, Zhi-Hai Zhong, Peng-Fei Gao, Wen-Zong Gao.
      N6-methyladenosine (m6A) RNA methylation and its associated methyltransferase METTL3 play an important role in tumorigenesis of a series of tumors. However, dysregulation of METTL3 in gallbladder cancer (GBC) remains obscure. Here, we showed that upregulated METTL3 level predicted poor prognosis and correlated with increased lymphatic metastasis and high TNM stage. Functionally, we found that METTL3 could promote cell proliferation, invasion, and migration of GBC-SD and NOZ cells. Mechanistically, we revealed the METTL3-mediated m6A-modification profile in GBC cells and identified DUSP5 as the downstream gene of METTL3. METTL3 promoted the degradation of DUSP5 mRNA in a YTHDF2-dependent manner. Rescue assays showed that downregulation of DUSP5 could attenuate the knockdown METTL3-mediated inhibition of cell proliferation, invasion, and migration of GBC-SD and NOZ cells. Thus, our finding shows that elevated METTL3 expression contributes to tumor aggression in GBC, suggesting that METTL3 is a possible prognostic predictor and therapeutic target against GBC.
    DOI:  https://doi.org/10.1038/s41417-021-00406-5
  3. Cancer Cell Int. 2021 Nov 18. 21(1): 609
    RNA m6A methylation regulators in ovarian cancer.
    Jialu Guo, Jianfeng Zheng, Huizhi Zhang, Jinyi Tong.
      N6-methyladenosine (m6A) is the most abundant RNA modification of mammalian mRNAs and plays a vital role in many diseases, especially tumours. In recent years, m6A has become the topic of intense discussion in epigenetics. M6A modification is dynamically regulated by methyltransferases, demethylases and RNA-binding proteins. Ovarian cancer (OC) is a common but highly fatal malignancy in female. Increasing evidence shows that changes in m6A levels and the dysregulation of m6A regulators are associated with the occurrence, development or prognosis of OC. In this review, the latest studies on m6A and its regulators in OC have been summarized, and we focus on the key role of m6A modification in the development and progression of OC. Additionally, we also discuss the potential use of m6A modification and its regulators in the diagnosis and treatment of OC.
    Keywords:  Biomarker; N6-methyladenosine; Ovarian cancer; Regulators
    DOI:  https://doi.org/10.1186/s12935-021-02318-8
  4. Neoplasma. 2021 Nov 16. pii: 210716N967. [Epub ahead of print]
    FTO demethylates YAP mRNA promoting oral squamous cell carcinoma tumorigenesis.
    Dian-Qi Li, Ci-Cheng Huang, Guang Zhang, Lei-Lei Zhou.
      N6-methyladenosine (m6A) is the most common internal reversible modification of mRNA, which occurs on the N6 nitrogen of adenosine. Fat mass and obesity-associated (FTO) is a demethylase that erases m6A modification and has recently been linked to cancer. Herein, we explored the role of FTO in oral squamous cell carcinoma (OSCC). High FTO mRNA and protein levels were observed in OSCC cell lines and tissues as compared to normal controls. OSCC patients with high FTO displayed larger tumor size, higher TNM stage, poorer differentiation, and shorter survival time than those with low FTO. Stable knockdown of FTO inhibited OSCC cell viability, colony formation, and tumor growth. Further, FTO depletion increased YAP1 m6A modification at mRNA 3'-untranslated region, accelerating the degradation of YAP1 mRNA, a well-documented oncogene promoting OSCC progression. Importantly, nucleocytoplasmic shuttling of FTO is critical for YAP1 mRNA demethylation and decay following YTHDF2 reading and recognition. Our results highlight the role of FTO in regulating YAP1 mRNA stability, and targeting of FTO/YAP1 axis may be a promising intervention for OSCC patients.
    DOI:  https://doi.org/10.4149/neo_2021_210716N967
  5. Bioengineered. 2021 Nov 17.
    Demethyltransferase FTO alpha-ketoglutarate dependent dioxygenase (FTO) regulates the proliferation, migration, invasion and tumor growth of prostate cancer by modulating the expression of melanocortin 4 receptor (MC4R).
    Sheng Li, Lin Cao.
      N6-Methyladenosine (m6A) is the most abundant modifications in human messenger RNAs (mRNAs). This study aimed at investigating the function and mechanism of demethyltransferase fat mass and obesity-associated protein (FTO) in prostate cancer(PCa). The expression level of FTO in PCa was detected by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and western blot. Besides, the impacts of FTO on the proliferation, migration and invasion of PCa cells were also detected by cell counting kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU) and transwell assays. Furthermore, we also explored the potential mechanism of FTO in PCa. The results showed that FTO expression was decreased in PCa, and the low expression of FTO showed an obvious relevance to the clinical characteristics. Downregulation of FTO facilitated the proliferation, migration, invasion and tumor growth of PCa cells. Besides, MC4R displayed a remarkably high expression in PCa tissues, whose expression and m6A level were regulated by FTO. Meanwhile, the in vitro experiments revealed that highly expressed FTO partially reversed the facilitating effect of highly expressed MC4R on the malignant phenotype of PCa cells. Overall, FTO was downregulated in PCa and its expression level showed a relevance to the prognosis of PCa patients. Additionally, FTO could regulate the proliferation, migration and invasion of PCa via regulating the expression level of MC4R.
    Keywords:  FTO; M6A; MC4R; Malignant progression; Prostate cancer
    DOI:  https://doi.org/10.1080/21655979.2021.2001936
  6. J Dent Res. 2021 Nov 19. 220345211051594
    METTL3-Dependent Glycolysis Regulates Dental Pulp Stem Cell Differentiation.
    W Cai, Y Ji, L Han, J Zhang, Y Ni, Y Cheng, Y Zhang.
      N6-methyladenosine (m6A) is a eukaryotic messenger RNA modification catalyzed by methyltransferase-like 3 (METTL3), which is involved in various developmental and disease processes. However, the connection between the epigenetic modification of m6A and glucose metabolism during osteogenesis is still unclear. Here, we show that interference with METTL3 in dental pulp stem cells (DPSCs) inhibits cell proliferation and osteogenic differentiation. Moreover, transcriptome sequencing and metabolic testing were used to explore the mechanism between glucose metabolism and m6A modification in METTL3-knockdown DPSCs. Methylated RNA immunoprecipitation-quantitative polymerase chain reaction and RNA stability assays were used to determine the target genes of METTL3. Mechanistically, METTL3 directly interacts with ATP citrate lyase (ACLY) and a mitochondrial citrate transporter (SLC25A1) and then further affects the glycolytic pathway. M6A-mediated ACLY and SLC25A1 stability depends on the m6A readers IGF2BP2 and IGF2BP2/3, respectively. Our experiments uncovered the potential molecular mechanism of epigenetic modification in osteogenic differentiation, providing new ideas for the clinical application of stem cells and the intervention of metabolic bone diseases.
    Keywords:  gene expression; growth/development; metabolism; modification; osteoblasts; osteogenesis
    DOI:  https://doi.org/10.1177/00220345211051594
  7. Front Cell Dev Biol. 2021 ;9 720925
    The RNA Methyltransferase METTL3 Promotes Endothelial Progenitor Cell Angiogenesis in Mandibular Distraction Osteogenesis via the PI3K/AKT Pathway.
    Weidong Jiang, Peiqi Zhu, Fangfang Huang, Zhenchen Zhao, Tao Zhang, Xiaoning An, Fengchun Liao, Lina Guo, Yan Liu, Nuo Zhou, Xuanping Huang.
      Distraction osteogenesis (DO) is used to treat large bone defects in the field of oral and maxillofacial surgery. Successful DO-mediated bone regeneration is dependent upon angiogenesis, and endothelial progenitor cells (EPCs) are key mediators of angiogenic processes. The N6-methyladenosine (m6A) methyltransferase has been identified as an important regulator of diverse biological processes, but its role in EPC-mediated angiogenesis during DO remains to be clarified. In the present study, we found that the level of m6A modification was significantly elevated during the process of DO and that it was also increased in the context of EPC angiogenesis under hypoxic conditions, which was characterized by increased METTL3 levels. After knocking down METTL3 in EPCs, m6A RNA methylation, proliferation, tube formation, migration, and chicken embryo chorioallantoic membrane (CAM) angiogenic activity were inhibited, whereas the opposite was observed upon the overexpression of METTL3. Mechanistically, METTL3 silencing reduced the levels of VEGF and PI3Kp110 as well as the phosphorylation of AKT, whereas METTL3 overexpression reduced these levels. SC79-mediated AKT phosphorylation was also able to restore the angiogenic capabilities of METTL3-deficient EPCs in vitro and ex vivo. In vivo, METTL3-overexpressing EPCs were additionally transplanted into the DO callus, significantly enhancing bone regeneration as evidenced by improved radiological and histological manifestations in a canine mandibular DO model after consolidation over a 4-week period. Overall, these results indicate that METTL3 accelerates bone regeneration during DO by enhancing EPC angiogenesis via the PI3K/AKT pathway.
    Keywords:  METTL3; PI3K/AKT signaling pathway; angiogenesis; distraction osteogenesis; endothelial progenitor cells
    DOI:  https://doi.org/10.3389/fcell.2021.720925
  8. Mol Med. 2021 Nov 13. 27(1): 146
    ADSCs enhance VEGFR3-mediated lymphangiogenesis via METTL3-mediated VEGF-C m6A modification to improve wound healing of diabetic foot ulcers.
    Jie Zhou, Tianhong Wei, Zhiyou He.
       BACKGROUND: Adipose-derived mesenchymal stem cells (ADSCs) are an important focus in regenerative medicine. However, the biological function of ADSCs in the wound repair of diabetic foot ulcers (DFUs) remains unclear. This study aimed to determine the underlying mechanisms of ADSCs involved in the wound healing of DFUs.
    METHODS: The cell surface markers cluster of differentiation 34 (CD34), stromal cell antigen 1 (Stro-1), cluster of differentiation 90 (CD90) and cluster of differentiation 105 (CD105) on ADSCs were identified by flow cytometry. Oil Red O staining and Alizarin Red S staining were performed to identify the multipotential differentiation of ADSCs into adipocytes and bone. The levels of Methyltransferase-like 3 (METTL3), vascular endothelial growth factor C (VEGF-C) and insulin-like growth factor 2 binding protein 2 (IGF2BP2) were assessed by RT-qPCR. CCK-8, Transwell and tubule formation assays were conducted to assess lymphatic endothelial cell (LEC) viability, migration and tubule formation ability, respectively. RIP and RNA pulldown assays were conducted to assess the interaction between IGF2BP2 and VEGF-C. The levels of VEGF-C, VEGFR3, LYVE-1 and IGF2BP2 proteins were assessed by Western blotting. The levels of VEGF-C in LECs were measured by ELISA.
    RESULTS: Our findings illustrated that ADSCs accelerate LEC proliferation, migration and lymphangiogenesis via the METTL3 pathway and regulate VEGF-C expression via the METTL3/IGF2BP2-m6A pathway VEGF-C-mediated lymphangiogenesis via the METTL3/IGF2BP2-m6A pathway in DFU mice.
    CONCLUSION: ADSCs enhance VEGFR3-mediated lymphangiogenesis via METTL3-mediated VEGF-C m6A modification to improve wound healing in DFUs, indicating that ADSCs may be regarded as a promising therapeutic strategy to promote wound healing in DFUs.
    Keywords:  ADSCs; DFU; Wound healing
    DOI:  https://doi.org/10.1186/s10020-021-00406-z
  9. Am J Transl Res. 2021 ;13(10): 11209-11222
    m(6)A demethylase ALKBH5 inhibits cell proliferation and the metastasis of colorectal cancer by regulating the FOXO3/miR-21/SPRY2 axis.
    Xiangbin Wu, Minzhi Dai, Jinlei Li, Jianhui Cai, Zhigui Zuo, Shichang Ni, Qiyu Zhang, Zhenhua Zhou.
       OBJECTIVE: Colorectal cancer is a common malignancy worldwide. This research aimed to investigate the role of α-ketoglutarate-dependent dioxygenase alkB homologue 5 (ALKBH5), a N6-methyladenosine (m(6)A) demethylase, on the cell proliferation and metastasis of colorectal cancer.
    METHODS: The interaction relationship between FOXO3, miR-21, and SPRY2 were predicted by starBase 2.0 and determined using RIP, CHIP, and dual-luciferase reporter assays. Quantitative reverse transcription PCR (RT-qPCR) and western blot were used to measure the gene and miRNA expressions of ALKBH5, FOXO3, miR-21, and SPRY2. The cell proliferation was determined using CCK8 and colony formation assays. The metastatic abilities were measured using wound healing and transwell assays.
    RESULTS: In colorectal cancer, downregulated ALKBH5 is related to poor prognosis. Rescued ALKBH5 suppresses the proliferation and metastasis of colorectal cancer cells. The role of ALKBH5 is achieved by reducing the m(6)A modification of forkhead box O3 (FOXO3), which enhances its stability. FOXO3 targets miR-21 and increases the SPRY2 expressions. The antitumor effects of ALKBH5 can be blocked by FOXO3 knockdown, which is reversed by the miR-21 inhibitor.
    CONCLUSION: ALKBH5 plays an antitumor role in colorectal cancer by regulating the FOXO3/miR-21/SPRY2 axis, providing a new direction for colorectal cancer therapy.
    Keywords:  N6-methyladenosine modification; colorectal cancer; forkhead box O3; miR-21; α-ketoglutarate-dependent dioxygenase alkB homologue 5
  10. Front Immunol. 2021 ;12 746647
    Comprehensive of N1-Methyladenosine Modifications Patterns and Immunological Characteristics in Ovarian Cancer.
    Jinhui Liu, Can Chen, Yichun Wang, Cheng Qian, Junting Wei, Yan Xing, Jianling Bai.
       Background: recently, many researches have concentrated on the relevance between N1-methyladenosine (m1A) methylation modifications and tumor progression and prognosis. However, it remains unknown whether m1A modification has an effect in the prognosis of ovarian cancer (OC) and its immune infiltration.
    Methods: Based on 10 m1A modulators, we comprehensively assessed m1A modification patterns in 474 OC patients and linked them to TME immune infiltration characteristics. m1Ascore computed with principal component analysis algorithm was applied to quantify m1A modification pattern in OC patients. m1A regulators protein and mRNA expression were respectively obtained by HPA website and RT-PCR in clinical OC and normal samples.
    Results: We finally identified three different m1A modification patterns. The immune infiltration features of these m1A modification patterns correspond to three tumor immune phenotypes, including immune-desert, immune-inflamed and immune-excluded phenotypes. The results demonstrate individual tumor m1A modification patterns can predict patient survival, stage and grade. The m1Ascore was calculated to quantify individual OC patient's m1A modification pattern. A high m1Ascore is usually accompanied by a better survival advantage and a lower mutational load. Research on m1Ascore in the treatment of OC patients showed that patients with high m1Ascore showed marked therapeutic benefits and clinical outcomes in terms of chemotherapy and immunotherapy. Lastly, we obtained four small molecule drugs that may potentially ameliorate prognosis.
    Conclusion: This research demonstrates that m1A methylation modification makes an essential function in the prognosis of OC and in shaping the immune microenvironment. Comprehensive evaluation of m1A modifications improves our knowledge of immune infiltration profile and provides a more efficient individualized immunotherapy strategy for OC patients.
    Keywords:  immune checkpoint blockade; m1A modification; ovarian cancer; prognosis; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2021.746647
  11. Mol Cell. 2021 Nov 08. pii: S1097-2765(21)00910-2. [Epub ahead of print]
    Balancing of mitochondrial translation through METTL8-mediated m3C modification of mitochondrial tRNAs.
    Eva Schöller, James Marks, Virginie Marchand, Astrid Bruckmann, Christopher A Powell, Markus Reichold, Christian Daniel Mutti, Katja Dettmer, Regina Feederle, Stefan Hüttelmaier, Mark Helm, Peter Oefner, Michal Minczuk, Yuri Motorin, Markus Hafner, Gunter Meister.
      Mitochondria contain a specific translation machinery for the synthesis of mitochondria-encoded respiratory chain components. Mitochondrial tRNAs (mt-tRNAs) are also generated from the mitochondrial DNA and, similar to their cytoplasmic counterparts, are post-transcriptionally modified. Here, we find that the RNA methyltransferase METTL8 is a mitochondrial protein that facilitates 3-methyl-cytidine (m3C) methylation at position C32 of the mt-tRNASer(UCN) and mt-tRNAThr. METTL8 knockout cells show a reduction in respiratory chain activity, whereas overexpression increases activity. In pancreatic cancer, METTL8 levels are high, which correlates with lower patient survival and an enhanced respiratory chain activity. Mitochondrial ribosome profiling uncovered mitoribosome stalling on mt-tRNASer(UCN)- and mt-tRNAThr-dependent codons. Further analysis of the respiratory chain complexes using mass spectrometry revealed reduced incorporation of the mitochondrially encoded proteins ND6 and ND1 into complex I. The well-balanced translation of mt-tRNASer(UCN)- and mt-tRNAThr-dependent codons through METTL8-mediated m3C32 methylation might, therefore, facilitate the optimal composition and function of the mitochondrial respiratory chain.
    Keywords:  METTL8; RNA modification; m(3)C; mt-tRNA; translation
    DOI:  https://doi.org/10.1016/j.molcel.2021.10.018
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