bims-rimeca Biomed News
on RNA methylation in cancer
Issue of 2021‒09‒12
ten papers selected by
Sk Ramiz Islam
Saha Institute of Nuclear Physics
  1. m6A modification regulates lung fibroblast-to-myofibroblast transition through modulating KCNH6 mRNA translation.
  2. METTL14 promotes glomerular endothelial cell injury and diabetic nephropathy via m6A modification of α-klotho.
  3. The tumor-suppressive effects of alpha-ketoglutarate-dependent dioxygenase FTO via N6-methyladenosine RNA methylation on bladder cancer patients.
  4. RNA N6-methyladenosine demethylase FTO promotes osteoporosis through demethylating Runx2 mRNA and inhibiting osteogenic differentiation.
  5. m6A demethylase FTO suppresses pancreatic cancer tumorigenesis by demethylating PJA2 and inhibiting Wnt signaling.
  6. ALKBH5-HOXA10 loop-mediated JAK2 m6A demethylation and cisplatin resistance in epithelial ovarian cancer.
  7. Long non-coding RNA ILF3-AS1 facilitates hepatocellular carcinoma progression by stabilizing ILF3 mRNA in an m6A-dependent manner.
  8. Cross-Talk between Oxidative Stress and m6A RNA Methylation in Cancer.
  9. METTL3-Mediated lncRNA m6A Modification in the Osteogenic Differentiation of Human Adipose-Derived Stem Cells Induced by NEL-Like 1 Protein.
  10. Regulatory role and mechanism of m6A RNA modification in human metabolic diseases.
  1. Mol Ther. 2021 Jun 08. pii: S1525-0016(21)00314-2. [Epub ahead of print]
    m6A modification regulates lung fibroblast-to-myofibroblast transition through modulating KCNH6 mRNA translation.
    Jia-Xiang Zhang, Pei-Jie Huang, Da-Peng Wang, Wen-Yu Yang, Jian Lu, Yong Zhu, Xiao-Xiao Meng, Xin Wu, Qiu-Hai Lin, Hui Lv, Hui Xie, Rui-Lan Wang.
      Idiopathic pulmonary fibrosis (IPF) is a chronic, fatal lung disease characterized by progressive and non-reversible abnormal matrix deposition in lung parenchyma. Myofibroblasts originating mainly from resident fibroblasts via fibroblast-to-myofibroblast transition (FMT) are the dominant collagen-producing cells in pulmonary fibrosis. N6-methyladenosine (m6A) modification has been implicated in various biological processes. However, the role of m6A modification in pulmonary fibrosis remains elusive. In this study, we reveal that m6A modification is upregulated in a bleomycin (BLM)-induced pulmonary fibrosis mouse model, FMT-derived myofibroblasts, and IPF patient lung samples. Lowering m6A levels through silencing methyltransferase-like 3 (METTL3) inhibits the FMT process in vitro and in vivo. Mechanistically, KCNH6 is involved in the m6A-regulated FMT process. m6A modification regulates the expression of KCNH6 by modulating its translation in a YTH-domain family 1 (YTHDF1)-dependent manner. Together, our study highlights the critical role of m6A modification in pulmonary fibrosis. Manipulation of m6A modification through targeting METTL3 may become a promising strategy for the treatment of pulmonary fibrosis.
    Keywords:  KCNH6; METTL3; YTHDF1; fibroblast-to-myofibroblast transition; m(6)A modification; pulmonary fibrosis
    DOI:  https://doi.org/10.1016/j.ymthe.2021.06.008
  2. Mol Med. 2021 Sep 09. 27(1): 106
    METTL14 promotes glomerular endothelial cell injury and diabetic nephropathy via m6A modification of α-klotho.
    Manna Li, Le Deng, Gaosi Xu.
      BACKGROUND: N6-Methyladenosine (m6A) modification has been implicated in many bioprocesses. However, its functions in diabetic nephropathy (DN) have not been determined. Here, we investigated the role of METTL14, a key component of the m6A methyltransferase complex, in DN.METHODS: The expression of METTL14 was detected in DN patients and human renal glomerular endothelial cells (HRGECs). In vitro and in vivo experiments were performed to explore the functions of METTL14 on high glocse-induced HRGECs and renal injury of DN mice. We also investigated whether METTL14 works by regulating α-klotho expression through m6A modification.
    RESULTS: METTL14 were highly expressed in kidneys of DN patients and high glocse-induced HRGECs both at the mRNA and protein level. Overexpression of METTL14 increased ROS, TNF-α and IL-6 levels and apoptosis in HRGECs. Conversely, METTL14 silence decreased the levels of ROS, TNF-α and IL-6 and cell apoptosis. We confirmed that METTL14 down-regulated α-klotho expression in an m6A-dependent manner. In addition, we also found that METTL14 aggravated renal injury and inflammation of db/db mice, which could partially rescued by α-klotho.
    CONCLUSION: Our data revealed that METTL14 plays a vital role in high glucose-induced glomerular endothelial cells and diabetic nephropathy through m6A modification of α-klotho.
    Keywords:  Diabetic nephropathy; Glomerular endothelial cell injury; METTL14; m6A; α-Klotho
    DOI:  https://doi.org/10.1186/s10020-021-00365-5
  3. Bioengineered. 2021 Dec;12(1): 5323-5333
    The tumor-suppressive effects of alpha-ketoglutarate-dependent dioxygenase FTO via N6-methyladenosine RNA methylation on bladder cancer patients.
    Wenfa Yi, Yong Yu, Yafei Li, Juan Yang, Shuying Gao, Lingfen Xu.
      N6-methyladenosine (m6A) methylation participates in the progression of bladder cancer (BCa). Nevertheless, the regulatory mechanism of alpha-ketoglutarate-dependent dioxygenase FTO influencing the BCa progression has still remained elusive. In this study, to investigate the tumor-suppressive effects of FTO via m6A RNA methylation on BCa patients, a total of 15 cancer tissues and adjacent normal tissues (ANTs) were collected from BCa patients who received tumor resection in our hospital from September 2015 to December 2019. We found that the FTO expression was significantly reduced in cancer tissues compared with that in ANTs, which indicated a lower malignant potential and a higher overall survival rate. It was revealed that overexpression of FTO in two human urinary BCa cell lines (HT-1197 and HT-1376) significantly decreased the cell proliferation and invasion abilities compared with the negative controls, whereas the cell apoptosis was markedly enhanced. In addition, we noted that the changes in m6A methylation level mainly appeared at 5' untranslated region (5' UTR) of MALAT1 and NOTCH1 transcripts, and at 3' UTR of CSNK2A2 and ITGA6 transcripts, responding to the overexpression of FTO. Mechanistically, we found that the splicing factor, proline- and glutamine-rich (SFPQ) could influence the FTO-mediated m6A RNA demethylation, eventually affecting the gene expression. This study provided a new insight into the relationship between the FTO expression and the m6A RNA methylation, assisting scholars to better understand the pathogenesis of BCa.
    Keywords:  FTO; bladder cancer; m6A rna methylation; sfpq
    DOI:  https://doi.org/10.1080/21655979.2021.1964893
  4. Aging (Albany NY). 2021 Sep 08. 13(undefined):
    RNA N6-methyladenosine demethylase FTO promotes osteoporosis through demethylating Runx2 mRNA and inhibiting osteogenic differentiation.
    Jing Wang, Qiang Fu, Jian Yang, Jin-Long Liu, Shu-Ming Hou, Xing Huang, Jia-Shi Cao, Tie-Long Liu, Kun-Zheng Wang.
      As a systemic disease, osteoporosis (OP) results in bone density loss and fracture risk, particularly in the hip and vertebrae. However, the underlying molecular mechanisms of OP development have not been fully illustrated. N6-Methyladenosine (m6A) is the most abundant modification of mRNAs, which is involved in many of pathological processes in aging disease. However, its role and regulatory mechanism in OP remains unknown. Here, we aimed to investigate the roles of m6A and its demethylase FTO in OP development. The results showed that m6A methylated RNA level was up-regulated in the bone marrow mesenchymal stem cells (BMSCs) from patients with OP. The level of N6-methyladenosine demethylase FTO was consistently decreased in the BMSCs from patients with OP. Functionally, lentivirus-mediated FTO overexpression in normal BMSCs to compromised osteogenic potential. Mechanism analysis further suggested that FTO overexpression decreased the m6A methylated and total level of runt related transcription factor 2 (Runx2) mRNA, subsequently inhibited osteogenic differentiation. We found that FTO inhibition could effectively improve the bone formation in ovariectomized osteoporotic mice in vivo. Together, these results reveal that RNA N6-methyladenosine demethylase FTO promotes osteoporosis through demethylating runx2 mRNA and inhibiting osteogenic differentiation.
    Keywords:  FTO; N6-methyladenosine (m6A); bone marrow mesenchymal stem cells; osteoporosis
    DOI:  https://doi.org/10.18632/aging.203377
  5. Mol Ther Nucleic Acids. 2021 Sep 03. 25 277-292
    m6A demethylase FTO suppresses pancreatic cancer tumorigenesis by demethylating PJA2 and inhibiting Wnt signaling.
    Juan Zeng, Heying Zhang, Yonggang Tan, Zhe Wang, Yunwei Li, Xianghong Yang.
      Pancreatic cancer is the deadliest malignancy of the digestive system and is the seventh most common cause of cancer-related deaths worldwide. The incidence and mortality of pancreatic cancer continue to increase, and its 5-year survival rate remains the lowest among all cancers. N6-methyladenine (m6A) is the most abundant reversible RNA modification in various eukaryotic messenger and long noncoding RNAs and plays crucial roles in the occurrence and development of cancers. However, the role of m6A in pancreatic cancer remains unclear. The present study aimed to explore the role of m6A and its regulators in pancreatic cancer and assess its underlying molecular mechanism associated with pancreatic cancer cell proliferation, invasion, and metastasis. Reduced expression of the m6A demethylase, fat mass and obesity-associated protein (FTO), was responsible for the high levels of m6A RNA modification in pancreatic cancer. Moreover, FTO demethylated the m6A modification of praja ring finger ubiquitin ligase 2 (PJA2), thereby reducing its mRNA decay, suppressing Wnt signaling, and ultimately restraining the proliferation, invasion, and metastasis of pancreatic cancer cells. Altogether, this study describes new, potential molecular therapeutic targets for pancreatic cancer that could pave the way to improve patient outcome.
    Keywords:  N6-methyladenine; PJA2; Wnt signaling; m6A demethylase FTO; pancreatic cancer
    DOI:  https://doi.org/10.1016/j.omtn.2021.06.005
  6. J Exp Clin Cancer Res. 2021 Sep 08. 40(1): 284
    ALKBH5-HOXA10 loop-mediated JAK2 m6A demethylation and cisplatin resistance in epithelial ovarian cancer.
    Sipei Nie, Lin Zhang, Jinhui Liu, Yicong Wan, Yi Jiang, Jing Yang, Rui Sun, Xiaolling Ma, Guodong Sun, Huangyang Meng, Mengting Xu, Wenjun Cheng.
      BACKGROUND: Chemotherapy resistance remains a barrier to improving the prognosis of epithelial ovarian cancer (EOC). ALKBH5 has recently been shown to be one of the RNA N6-methyladenosine (m6A) demethyltransferases associated with various cancers, but its role in cancer therapeutic resistance remains unclear. This study aimed to investigate the role of AlkB homolog 5 (ALKBH5) in cisplatin-resistant EOC.METHODS: Functional assays were performed both in vitro and in vivo. RNA sequencing (RNA-seq), m6A-modified RNA immunoprecipitation sequencing (MeRIP-seq), chromatin immunoprecipitation, RNA immunoprecipitation, and luciferase reporter and actinomycin-D assays were performed to investigate RNA/RNA interaction and m6A modification of the ALKBH5-HOXA10 loop.
    RESULTS: ALKBH5 was upregulated in cisplatin-resistant EOC and promoted cancer cell cisplatin resistance both in vivo and in vitro. Notably, HOXA10 formed a loop with ALKBH5 and was found to be the upstream transcription factor of ALKBH5. HOXA10 overexpression also facilitated EOC cell chemoresistance both in vivo and in vitro. Collective results of MeRIP-seq and RNA-seq showed that JAK2 is the m6A-modified gene targeted by ALKBH5. The JAK2/STAT3 signaling pathway was activated by overexpression of the ALKBH5-HOXA10 loop, resulting in EOC chemoresistance. Cell sensitivity to cisplatin was rescued by ALKBH5 and HOXA10 knockdown or inhibition of the JAK2/STAT3 signaling pathway in EOC cells overexpressing ALKBH5-HOXA10.
    CONCLUSIONS: The ALKBH5-HOXA10 loop jointly activates the JAK2/STAT3 signaling pathway by mediating JAK2 m6A demethylation, promoting EOC resistance to cisplatin. Thus, inhibition of the expression of the ALKBH5-HOXA10 loop may be a potential strategy to overcome cisplatin resistance in EOC.
    Keywords:  ALKBH5; Cisplatin resistance; Epithelial ovarian cancer; N6-methyladenosine
    DOI:  https://doi.org/10.1186/s13046-021-02088-1
  7. Hum Cell. 2021 Sep 07.
    Long non-coding RNA ILF3-AS1 facilitates hepatocellular carcinoma progression by stabilizing ILF3 mRNA in an m6A-dependent manner.
    Changwen Bo, Na Li, Li He, Sujing Zhang, Yonghui An.
      Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. Increasing evidences have demonstrated that ILF3 antisense RNA 1 (ILF3-AS1) acts as an oncogenic long noncoding RNA (lncRNA) in several types of human cancers. However, the expression pattern, functional role and underlying mechanism of ILF3-AS1 in HCC remains largely unclear. Here, we found that ILF3-AS1 expression was significantly elevated in HCC tissues and also associated with prognosis of patients with HCC. Functional assays demonstrated that knockdown of ILF3-AS1 expression resulted in the suppression of proliferation, migration and invasion in HCC cells, whereas overexpression of ILF3-AS1 exerted opposite effects. Additionally, knockdown of IFL3-AS1 attenuated HCC tumorigenesis and metastasis in vivo. Mechanistically, ILF3-AS1 associated with ILF3 mRNA and inhibited its degradation. ILF3-AS1 increased ILF3 m6A level via recruiting N6-methyladenosine (m6A) RNA methyltransferase METTL3. Moreover, IFL3-AS1 enhanced the interaction between ILF3 mRNA and m6A reader IGF2BP1. Overall, our study revealed the function and mechanism of ILF3-AS1 in the malignant phenotypes of HCC cells, which provides a novel therapeutic target for HCC.
    Keywords:  ILF3; lncRNA; m6A modification; mRNA stability
    DOI:  https://doi.org/10.1007/s13577-021-00608-x
  8. Oxid Med Cell Longev. 2021 ;2021 6545728
    Cross-Talk between Oxidative Stress and m6A RNA Methylation in Cancer.
    Baishuang Yang, Qiong Chen.
      Oxidative stress is a state of imbalance between oxidation and antioxidation. Excessive ROS levels are an important factor in tumor development. Damage stimulation and excessive activation of oncogenes cause elevated ROS production in cancer, accompanied by an increase in the antioxidant capacity to retain redox homeostasis in tumor cells at an increased level. Although moderate concentrations of ROS produced in cancer cells contribute to maintaining cell survival and cancer progression, massive ROS accumulation can exert toxicity, leading to cancer cell death. RNA modification is a posttranscriptional control mechanism that regulates gene expression and RNA metabolism, and m6A RNA methylation is the most common type of RNA modification in eukaryotes. m6A modifications can modulate cellular ROS levels through different mechanisms. It is worth noting that ROS signaling also plays a regulatory role in m6A modifications. In this review, we concluded the effects of m6A modification and oxidative stress on tumor biological functions. In particular, we discuss the interplay between oxidative stress and m6A modifications.
    DOI:  https://doi.org/10.1155/2021/6545728
  9. Stem Cell Rev Rep. 2021 Sep 10.
    METTL3-Mediated lncRNA m6A Modification in the Osteogenic Differentiation of Human Adipose-Derived Stem Cells Induced by NEL-Like 1 Protein.
    Yidan Song, Yihua Pan, Mengsong Wu, Wentian Sun, Liangyu Luo, Zhihe Zhao, Jun Liu.
      OBJECTIVES: This study aimed to explore the regulatory mechanism of methyltransferase3 (METTL3) -mediated long non-coding RNA (lncRNA) N6-methyladenosine (m6A) modification in the osteogenic differentiation of human adipose-derived stem cells (hASCs) induced by NEL-like 1 protein (NELL-1).MATERIALS AND METHODS: Methylated RNA immunoprecipitation sequencing (MeRIP-seq) and high- throughput sequencing for RNA (RNA-seq) were performed on hASCs. Osteogenic ability was detected by alkaline phosphatase (ALP) staining, Alizarin Red S(ARS) staining, ALP quantification and Quantitative real-time polymerase chain reaction analysis (qRT-PCR). Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis predicted the osteogenesis-related pathways enriched for the lncRNAs and identified the target lncRNAs. After overexpression and knockdown of METTL3, methylated RNA immunoprecipitation-qPCR (MeRIP-qPCR) and qRT-PCR were used to detect the levels of m6A modification and the expression of the target lncRNA, and the binding of both was confirmed by RNA binding protein immunoprecipitation (RIP) assay. The effects of lncRNA and METTL3 on phosphorylation of the key proteins of the pathway were detected by western blot analysis.
    RESULTS: In vitro experiments showed that METTL3 can promote osteogenic differentiation and that its expression level is upregulated. KEGG pathway analysis predicted that lncRNAs with differentially upregulated methylated peaks were enriched mostly in the mitogen-activated protein kinase (MAPK) signaling pathway, in which Serine/threonine protein kinase 3 (STK3) was the predicted target gene of the lncRNA RP11-44 N12.5. The m6A modification and expression of RP11-44 N12.5 were both regulated by METTL3. Subsequently, lncRNA RP11-44 N12.5 and METTL3 were found to regulate the phosphorylation levels of three key proteins in the MAPK signaling pathway, ERK, JNK and p38.
    CONCLUSIONS: This study shows, for the first time, that METTL3 can activate the MAPK signaling pathway by regulating the m6A modification and expression of a lncRNA, thereby enhancing the osteogenic differentiation of hASCs.
    Keywords:  METTL3; NEL-like 1 protein; Osteogenic differentiation; lncRNA; m6A modification
    DOI:  https://doi.org/10.1007/s12015-021-10245-4
  10. Mol Ther Oncolytics. 2021 Sep 24. 22 52-63
    Regulatory role and mechanism of m6A RNA modification in human metabolic diseases.
    Yuliang Zhang, Wenjie Chen, Xiwang Zheng, Yujia Guo, Jimin Cao, Yu Zhang, Shuxin Wen, Wei Gao, Yongyan Wu.
      Metabolic diseases caused by disorders in amino acids, glucose, lipid metabolism, and other metabolic risk factors show high incidences in young people, and current treatments are ineffective. N 6-methyladenosine (m6A) RNA modification is a post-transcriptional regulation of gene expression with several effects on physiological processes and biological functions. Recent studies report that m6A RNA modification is involved in various metabolic pathways and development of common metabolic diseases, making it a potential disease-specific therapeutic target. This review explores components, mechanisms, and research methods of m6A RNA modification. In addition, we summarize the progress of research on m6A RNA modification in metabolism-related human diseases, including diabetes, obesity, non-alcoholic fatty liver disease, osteoporosis, and cancer. Furthermore, opportunities and the challenges facing basic research and clinical application of m6A RNA modification in metabolism-related human diseases are discussed. This review is meant to enhance our understanding of the molecular mechanisms, research methods, and clinical significance of m6A RNA modification in metabolism-related human diseases.
    Keywords:  amino acid metabolism; glucose metabolism; lipid metabolism; m6A RNA modification; metabolic disease
    DOI:  https://doi.org/10.1016/j.omto.2021.05.003
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