bims-rimeca Biomed News
on RNA methylation in cancer
Issue of 2021–12–19
ten papers selected by
Sk Ramiz Islam, Saha Institute of Nuclear Physics
  1. METTL14 benefits the mesenchymal stem cells in patients with steroid-associated osteonecrosis of the femoral head by regulating the m6A level of PTPN6.
  2. Activation of YAP1 by N6-methyladenosine-modified CircCPSF6 Drives Malignancy in Hepatocellular Carcinoma.
  3. LncRNA CASC11 Promotes Hepatocellular Carcinoma Progression via Upregulation of UBE2T in a m6A-Dependent Manner.
  4. The N6-methyladenosine reader protein YTHDC2 promotes gastric cancer progression via enhancing YAP mRNA translation.
  5. FTO promotes multiple myeloma progression by posttranscriptional activation of HSF1 in an m6A-YTHDF2-dependent manner.
  6. Increased METTL3-mediated m6A methylation inhibits embryo implantation by repressing HOXA10 expression in recurrent implantation failure.
  7. HILIC-MS/MS for the Determination of Methylated Adenine Nucleosides in Human Urine.
  8. TCF4 and HuR mediated-METTL14 suppresses dissemination of colorectal cancer via N6-methyladenosine-dependent silencing of ARRDC4.
  9. N6-methyladenosine-mediated downregulation of miR-374c-5p promotes cadmium-induced cell proliferation and metastasis by targeting GRM3 in breast cancer cells.
  10. The Prognostic Value and Immune Landscapes of a m6A/m5C/m1A-Related LncRNAs Signature in Head and Neck Squamous Cell Carcinoma.
  1. Aging (Albany NY). 2021 Dec 15. 13(undefined):
    METTL14 benefits the mesenchymal stem cells in patients with steroid-associated osteonecrosis of the femoral head by regulating the m6A level of PTPN6.
    Cheng Cheng, Haoping Zhang, Jia Zheng, Yi Jin, Donghui Wang, Zhipeng Dai.
      Imbalanced osteogenic/adipogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) is considered the core pathological characteristic of steroid-associated osteonecrosis of the femoral head (SONFH). N6-Methyladenosine (m6A) is the most common type of RNA modification in eukaryotic cells and participates in various physiological and pathological processes. However, the relationship between m6A modification and SONFH has not been reported. In the present study, we aimed to explore the roles of m6A modifications and methyltransferase METTL14 in SONFH. Our results showed that the m6A levels were down-regulated in femoral head tissues and BMSCs from SONFH patients, and this effect was attributed to the reduction of METTL14. Furthermore, METTL14 overexpression in BMSCs from SONFH patients enhanced cell proliferation and osteogenic differentiation. We further identified PTPN6 as the downstream target of METTL14 by mRNA sequencing. Mechanistically, METTL14 regulated PTPN6 expression by increasing PTPN6 mRNA stability in an m6A-dependent manner. Moreover, PTPN6 knockdown abrogated the beneficial effects of METTL14 overexpression on BMSCs. Additionally, we found that METTL14 activated the Wnt signaling pathway, and this effect was caused by the interaction of PTPN6 and GSK-3β. In conclusion, we elucidated the functional roles of METTL14 and m6A methylation in SONFH BMSCs and identified a novel RNA regulatory mechanism, providing a potential therapeutic target for SONFH.
    Keywords:  METTL14; Wnt signaling pathway; m6A; mesenchymal stem cell; osteonecrosis of the femoral head
    DOI:  https://doi.org/10.18632/aging.203778
  2. Cancer Res. 2021 Dec 16. pii: canres.1628.2021. [Epub ahead of print]
    Activation of YAP1 by N6-methyladenosine-modified CircCPSF6 Drives Malignancy in Hepatocellular Carcinoma.
    Yunhao Chen, Zhenan Ling, Xianlei Cai, Yongfang Xu, Zhen Lv, Da Man, Jiangzhen Ge, Chengkuan Yu, Deguo Zhang, Yanpeng Zhang, Haiyang Xie, Lin Zhou, Jian Wu, Shusen Zheng.
      Circular RNAs (circRNAs) and N6-methyladenosine (m6A) modification are extensively involved in the progression of diverse tumors, including hepatocellular carcinoma (HCC). However, the crosstalk between circRNAs and m6A remains elusive in the pathogenesis of HCC. Here we investigated m6A-mediated regulation of circRNAs in HCC. M6A-related circRNAs were identified by integrating information from two published studies, revealing circular cleavage and polyadenylation specific factor 6 (circCPSF6) as a novel m6A-modified circRNA. CircCPSF6 was dominated by ALKBH5-mediated demethylation, followed by the recognization and destabilization by YTHDF2. Meanwhile, circCPSF6 was upregulated in HCC specimens, and elevated circCPSF6 expression served as an independent prognostic factor for worse survival of HCC patients. Loss-of-function assays demonstrated that circCPSF6 maintained cell proliferation and tumorigenicity and reinforced cell motility and tumor metastasis. CircCPSF6 triggered expression of YAP1, further activating its downstream cascade. Mechanistically, circCPSF6 competitively bound PCBP2, blunting its binding to YAP1 mRNA, thereby sustaining the stability of YAP1. Functionally, removal of YAP1 reversed the effects of circCPSF6 in vitro and in vivo. Aberrant activation of the circCPSF6-YAP1 axis promoted HCC malignancy. These findings offer novel insights into the regulation of circRNAs by m6A modifications and the role of this epigenetic reprogramming in HCC.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-1628
  3. Front Oncol. 2021 ;11 772671
    LncRNA CASC11 Promotes Hepatocellular Carcinoma Progression via Upregulation of UBE2T in a m6A-Dependent Manner.
    Fei Chen, Meijun Li, Liang Wang.
      Hepatocellular carcinoma (HCC) is one of the most frequent malignancies and the third leading cause of cancer-related deaths worldwide. Besides, it has been revealed that long non-coding RNA (LncRNA) cancer susceptibility candidate 11 (CASC11) is involved in cancer progression. However, the functional role and underlying mechanism of CASC11 in HCC remains largely unknown. In this context, here, it was found that CASC11 was upregulated in HCC tissues and associated with tumor grades, metastasis, and prognosis of HCC patients. Functionally, CASC11 facilitated HCC cell proliferation, migration, and invasion in vitro, and enhanced tumor growth and metastasis in vivo. Mechanistically, CASC11 associated with and stabilized Ubiquitin-conjugating enzyme E2T (UBE2T) mRNA. To be specific, it decreased UBE2T N6-methyladenosine (m6A) level via recruiting ALKBH5. Moreover, CASC11 inhibited the association between UBE2T mRNA and m6A reader protein YTHDF2. Taken together, our findings demonstrate the epigenetic mechanism of CASC11 in the regulation of UBE2T expression and possibly provide a novel therapeutic target for HCC treatment.
    Keywords:  ALKBH5; RNA methylation; UBE2T; mRNA stability; posttranscriptional regulation
    DOI:  https://doi.org/10.3389/fonc.2021.772671
  4. Transl Oncol. 2021 Dec 12. pii: S1936-5233(21)00299-0. [Epub ahead of print]16 101308
    The N6-methyladenosine reader protein YTHDC2 promotes gastric cancer progression via enhancing YAP mRNA translation.
    Wei Yuan, Shiqiang Chen, Bo Li, Xiaoyu Han, Bo Meng, Yongping Zou, Shunwu Chang.
      N6-methyladenosine (m6A) modification is the most prevalent internal modification in eukaryotic mRNA. YTH domain containing 2 (YTHDC2), a m6A binding protein, has recently been identified as a key player in human cancer. However, its contribution to gastric cancer (GC) remains unknown. Herein, we found that YTHDC2 was significantly upregulated in human GC tissues and associated with poor prognosis. CRISPR-Cas9 mediated YTHDC2 knockout notably inhibited GC cell viability, proliferation and invasion. Transcriptome analysis coupled with mechanism experiments revealed that yes-associated protein (YAP), the well-known oncogene, is the target of YTHDC2 in GC cells. Specifically, YTHDC2 recognized m6A-modified YAP mRNA at 5`-UTR, resulting in enhancing the translation efficiency of YAP, without affecting its mRNA level. In turn, YAP/TEAD directly targeted -843∼-831 region on the promoter of YTHDC2 and activated the transcription of YTHDC2, thus forming a positive regulatory loop. Further, using the xenograft tumor model, we found that knockout of YTHDC2 markedly reduced tumor size and lung metastasis nodules in vivo. And high YTHDC2 was strongly positively correlated with high YAP in clinical GC tissues. Collectively, our data demonstrate that YTHDC2 is a novel oncogene in GC, which provides the theoretical basis for the strategy of targeting YTHDC2 for GC patients.
    Keywords:  Biomarker; Translation regulator; YAP; YTHDC2; m(6)A
    DOI:  https://doi.org/10.1016/j.tranon.2021.101308
  5. Mol Ther. 2021 Dec 13. pii: S1525-0016(21)00648-1. [Epub ahead of print]
    FTO promotes multiple myeloma progression by posttranscriptional activation of HSF1 in an m6A-YTHDF2-dependent manner.
    Aoshuang Xu, Jiasi Zhang, Liping Zuo, Han Yan, Lei Chen, Fei Zhao, Fengjuan Fan, Jian Xu, Bo Zhang, Yuyang Zhang, Xuejiao Yin, Qianwen Cheng, Su Gao, Jun Deng, Heng Mei, Zhiping Huang, Chunyan Sun, Yu Hu.
      N6-methyladenosine (m6A) as the most pervasive internal modification of eukaryotic mRNA, plays a crucial role in various cancers, but its role in multiple myeloma (MM) pathogenesis has not yet been investigated. In this study, we revealed significantly decreased m6A methylation in plasma cells from MM patients and showed that the abnormal m6A level resulted mainly from upregulation of the demethylase fat mass and obesity-associated protein (FTO). Gain- and loss-of-function studies demonstrated that FTO plays a tumor-promoting and pro-metastatic role in MM. Combined m6A and RNA sequencing and subsequent validation and functional studies identified heat shock factor 1 (HSF1) as a functional target of FTO-mediated m6A modification. FTO significantly promotes MM cells proliferation, migration and invasion by targeting HSF1/HSPs in a YTHDF2-dependent manner. FTO inhibition, especially when combined with bortezomib treatment, synergistically inhibited myeloma bone tumor formation and extramedullary spread in NOD-Prkdcem26Cd52il2rgem26Cd22/Nju (NCG) mice. We demonstrated the functional importance of m6A demethylase FTO in MM progression, especially in promoting extramedullary myeloma formation and proposed the FTO-HSF1/HSP axis as a potential novel therapeutic target in MM.
    Keywords:  FTO; HSF1; m(6)A methylation; metastasis; multiple myeloma
    DOI:  https://doi.org/10.1016/j.ymthe.2021.12.012
  6. Reprod Biol Endocrinol. 2021 Dec 14. 19(1): 187
    Increased METTL3-mediated m6A methylation inhibits embryo implantation by repressing HOXA10 expression in recurrent implantation failure.
    Pingping Xue, Wenbo Zhou, Wenqiang Fan, Jianya Jiang, Chengcai Kong, Wei Zhou, Jianmei Zhou, Xiaoyang Huang, Haiyan Yang, Qian Han, Bin Zhang, Lingyun Xu, Bin Yu, Li Chen.
       BACKGROUND: Recurrent implantation failure (RIF) is a major limitation of assisted reproductive technology, which is associated with impaired endometrial receptivity. Although N6-methyladenosine (m6A) has been demonstrated to be involved in various biological processes, its potential role in the endometrium of women with RIF has been poorly studied.
    METHODS: Global m6A levels and major m6A methyltransferases/demethylases mRNA levels in mid-secretory endometrium from normal and RIF women were examined by colorimetric m6A quantification strategy and quantitative real-time PCR, respectively. The effects of METTL3-mediated m6A modification on embryo attachment were evaluated by an vitro model of a confluent monolayer of Ishikawa cells co-cultured with BeWo spheroids, and the expression levels of homeo box A10 (HOXA10, a well-characterized marker of endometrial receptivity) and its downstream targets were evaluated by quantitative real-time PCR and Western blotting in METTL3-overexpressing Ishikawa cells. The molecular mechanism for METTL3 regulating HOXA10 expression was determined by methylated RNA immunoprecipitation assay and transcription inhibition assay.
    RESULTS: Global m6A methylation and METTL3 expression were significantly increased in the endometrial tissues from women with RIF compared with the controls. Overexpression of METTL3 in Ishikawa cells significantly decreased the ration of BeWo spheroid attachment, and inhibited HOXA10 expression with downstream decreased β3-integrin and increased empty spiracles homeobox 2 expression. METTL3 catalyzed the m6A methylation of HOXA10 mRNA and contributed to its decay with shortened half-life. Enforced expression of HOXA10 in Ishikawa cells effectively rescued the impairment of METTL3 on the embryo attachment in vitro.
    CONCLUSION: Increased METTL3-mediated m6A modification represents an adverse impact on embryo implantation by inhibiting HOXA10 expression, contributing to the pathogenesis of RIF.
    Keywords:  HOXA10; METTL3; embryo implantation; m6A methylation; recurrent implantation failure
    DOI:  https://doi.org/10.1186/s12958-021-00872-4
  7. Anal Chem. 2021 Dec 13.
    HILIC-MS/MS for the Determination of Methylated Adenine Nucleosides in Human Urine.
    Cheng Guo, Yiqiu Hu, Xiaoji Cao, Yinsheng Wang.
      N6-methyl-2'-deoxyadenosine (m6dA) is a newly discovered DNA epigenetic mark in mammals. N6-methyladenosine (m6A), 2'-O-methyladenosine (Am), N6,2'-O-dimethyladenosine (m6Am), and N6,N6-dimethyladenosine (m62A) are common RNA modifications. Previous studies illustrated the associations between the aberrations of these methylated adenosines in nucleic acids and cancer. Herein, we developed Fe3O4/graphene-based magnetic dispersive solid-phase extraction for the enrichment and hydrophilic interaction liquid chromatography-mass spectrometry (HILIC-MS/MS) for the measurements of m6dA, m6A, Am, m6Am, and m62A in human urine samples. We found that malic acid could improve the HILIC-based separation of these modified nucleosides and markedly enhance the sensitivity of their MS detection. With this method, we accurately quantified the contents of these modified adenine nucleosides in urine samples collected from gastric and colorectal cancer patients as well as healthy controls. We found that, relative to healthy controls, urinary m6dA and Am levels are significantly lower for gastric and colorectal cancer patients; while gastric cancer patients also exhibited lower levels of urinary m6A, the trend was opposite for colorectal cancer patients. Together, we developed a robust analytical method for simultaneous measurements of five methylated adenine nucleosides in human urine, and our results revealed an association between the levels of urinary methylated adenine nucleosides and the occurrence of gastric as well as colorectal cancers, suggesting the potential applications of these modified nucleosides as biomarkers for the early detection of these cancers.
    DOI:  https://doi.org/10.1021/acs.analchem.1c03829
  8. Cell Death Dis. 2021 Dec 17. 13(1): 3
    TCF4 and HuR mediated-METTL14 suppresses dissemination of colorectal cancer via N6-methyladenosine-dependent silencing of ARRDC4.
    Hao Wang, Wei Wei, Zhong-Yuan Zhang, Yao Liu, Bin Shi, Wen Zhong, Hou-Shun Zhang, Xin Fang, Chun-Lei Sun, Jia-Bei Wang, Lian-Xin Liu.
      Metastasis remains the major obstacle to improved survival for colorectal cancer (CRC) patients. Dysregulation of N6-methyladenosine (m6A) is causally associated with the development of metastasis through poorly understood mechanisms. Here, we report that METTL14, a key component of m6A methylation, is functionally related to the inhibition of ARRDC4/ZEB1 signaling and to the consequent suppression of CRC metastasis. We unveil METTL14-mediated m6A modification profile and identify ARRDC4 as a direct downstream target of METTL14. Knockdown of METTL14 significantly enhanced ARRDC4 mRNA stability relying on the "reader" protein YHTDF2 dependent manner. Moreover, we demonstrate that TCF4 can induce METTL14 protein expression, and HuR suppress METTL14 expression by directly binding to its promoter. Clinically, our results show that decreased METTL14 is correlated with poor prognosis and acts as an independent predictor of CRC survival. Collectively, our findings propose that METTL14 functions as a metastasis suppressor, and define a novel signaling axis of TCF4/HuR-METTL14-YHTDF2-ARRDC4-ZEB1 in CRC, which might be potential therapeutic targets for CRC.
    DOI:  https://doi.org/10.1038/s41419-021-04459-0
  9. Ecotoxicol Environ Saf. 2021 Dec 14. pii: S0147-6513(21)01197-0. [Epub ahead of print]229 113085
    N6-methyladenosine-mediated downregulation of miR-374c-5p promotes cadmium-induced cell proliferation and metastasis by targeting GRM3 in breast cancer cells.
    Yang Yue, Ping Deng, Heng Xiao, Miduo Tan, Hui Wang, Li Tian, Jia Xie, Mengyan Chen, Yan Luo, Liting Wang, Yidan Liang, Huifeng Pi, Zhou Zhou, Zhengping Yu.
      Cadmium (Cd) is a toxic heavy metal that can facilitate the development and progression of breast cancer (BC). Emerging evidence has indicated that the progression of Cd-exposed BC is related to the dysregulation of microRNAs (miRNAs). The purpose of our study was to investigate the expression pattern and underlying mechanisms of miR-374c-5p in Cd-mediated BC progression. In this study, T-47D cells and MCF-7 cells were treated with different concentrations of Cd (0.1, 1 and 10 μM) for 72 h. MiR-374c-5p expression was downregulated, and transfection of miR-374c-5p mimics significantly decreased BC cell proliferation, migration and invasion induced by 10 μM Cd. Importantly, we used the Cytoscape software plugin cytoHubba to analyse the intersected genes between our RNA-Seq results and the mirDIP database, and six hub genes (CNR1, CXCR4, GRM3, RTN1, SLC1A6 and ZEB1) were identified as potential direct targets of miR-374c-5p in our model; however, luciferase reporter assays indicated that miR-374c-5p only repressed GRM3 by directly binding to its 3'-untranslated region (UTR). Of note, we verified that suppression of N6-methyladenosine (m6A) modification led to miR-374c-5p downregulation by decreasing its RNA transcript stability. Together, these findings demonstrated that m6A modification of pri-miRNA-374c blocks miRNA-374c-5p maturation and then activates GRM3 expression, which drives BC cell metastasis after Cd exposure.
    Keywords:  Breast cancer; Cadmium; GRM3; M6A; MiR-374c-5p
    DOI:  https://doi.org/10.1016/j.ecoenv.2021.113085
  10. Front Cell Dev Biol. 2021 ;9 718974
    The Prognostic Value and Immune Landscapes of a m6A/m5C/m1A-Related LncRNAs Signature in Head and Neck Squamous Cell Carcinoma.
    Enhao Wang, Yang Li, Ruijie Ming, Jiahui Wei, Peiyu Du, Peng Zhou, Shimin Zong, Hongjun Xiao.
      Background: N6-methyladenosine (m6A), 5-methylcytosine (m5C) and N1-methyladenosine (m1A) are the main RNA methylation modifications involved in the progression of cancer. However, it is still unclear whether m6A/m5C/m1A-related long non-coding RNAs (lncRNAs) affect the prognosis of head and neck squamous cell carcinoma (HNSCC). Methods: We summarized 52 m6A/m5C/m1A-related genes, downloaded 44 normal samples and 501 HNSCC tumor samples with RNA-seq data and clinical information from The Cancer Genome Atlas (TCGA) database, and then searched for m6A/m5C/m1A-related genes co-expressed lncRNAs. We adopt the least absolute shrinkage and selection operator (LASSO) Cox regression to obtain m6A/m5C/m1A-related lncRNAs to construct a prognostic signature of HNSCC. Results: This prognostic signature is based on six m6A/m5C/m1A-related lncRNAs (AL035587.1, AC009121.3, AF131215.5, FMR1-IT1, AC106820.5, PTOV1-AS2). It was found that the high-risk subgroup has worse overall survival (OS) than the low-risk subgroup. Moreover, the results showed that most immune checkpoint genes were significantly different between the two risk groups (p < 0.05). Immunity microenvironment analysis showed that the contents of NK cell resting, macrophages M2, and neutrophils in samples of low-risk group were significantly lower than those of high-risk group (p < 0.05), while the contents of B cells navie, plasma cells, and T cells regulatory (Tregs) were on the contrary (p < 0.05). In addition, patients with high tumor mutational burden (TMB) had the worse overall survival than those with low tumor mutational burden. Conclusion: Our study elucidated how m6A/m5C/m1A-related lncRNAs are related to the prognosis, immune microenvironment, and TMB of HNSCC. In the future, these m6A/m5C/m1A-related lncRNAs may become a new choice for immunotherapy of HNSCC.
    Keywords:  RNA methylation; epigenetic change; head and neck squamous cell carcinoma; long non-coding RNA; prognostic signature
    DOI:  https://doi.org/10.3389/fcell.2021.718974
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