bims-rimeca Biomed News
on RNA methylation in cancer
Issue of 2022–06–26
nine papers selected by
Sk Ramiz Islam, Saha Institute of Nuclear Physics
  1. Comprehensive immunohistochemical analysis of N6-methyladenosine (m6A) writers, erasers, and readers in endometrial cancer.
  2. FTO Prevents Thyroid Cancer Progression by SLC7A11 m6A Methylation in a Ferroptosis-Dependent Manner.
  3. Gene amplification-driven RNA methyltransferase KIAA1429 promotes tumorigenesis by regulating BTG2 via m6A-YTHDF2-dependent in lung adenocarcinoma.
  4. The m6A Methyltransferase METTL3-Mediated N6-Methyladenosine Modification of DEK mRNA to Promote Gastric Cancer Cell Growth and Metastasis.
  5. M6 A Demethylase FTO Regulates Cisplatin Resistance of Gastric Cancer by Modulating Autophagy Activation via ULK1.
  6. HIF-1α Regulated WTAP Overexpression Promoting the Warburg Effect of Ovarian Cancer by m6A-Dependent Manner.
  7. FTO-mediated m6 A modification of SOCS1 mRNA promotes the progression of diabetic kidney disease.
  8. The Methylation Game: Epigenetic and Epitranscriptomic Dynamics of 5-Methylcytosine.
  9. RNA modification patterns based on major RNA modifications define tumor microenvironment characteristics in glioblastoma.
  1. J Cancer Res Clin Oncol. 2022 Jun 22.
    Comprehensive immunohistochemical analysis of N6-methyladenosine (m6A) writers, erasers, and readers in endometrial cancer.
    Damian J Ralser, Mateja Condic, Niklas Klümper, Jörg Ellinger, Christian Staerk, Eva K Egger, Glen Kristiansen, Alexander Mustea, Thore Thiesler.
       PURPOSE: N6-methyladenosine (m6A) is the most frequent type of messenger RNA (mRNA) modification and is implicated in diverse physiological processes. The procedure of m6A RNA modification is regulated by a dynamic interaction of writers (METTL3, METTL4, METTL14, WTAP, KIAA1429), erasers (FTO, ALKBH5), and readers (HNRNPA2B1, HNRNPC, YTHDC1, YTHDC1, YTHDF1-3). In the oncological context, alterations in m6A were identified to be critically involved in tumorigenesis, proliferation, angiogenesis, and drug resistance across diverse cancer entities including endometrial cancer (EC).
    METHODS: In this study, we comprehensively examined the protein expression of m6A writers, readers and erasers by immunohistochemical staining in a cohort of N = 65 EC patients. Protein expression data were analyzed with regard to clinical outcomes.
    RESULTS: We identified enhanced protein expression levels of METTL3, METTL14, FTO, HNRNPA2B1, and HNRNPC, respectively to be of prognostic value and linked to a shortened overall survival in EC.
    CONCLUSION: Overall, our study points toward dysregulated m6A modification in EC and its possibility to serve as a promising prognostic biomarker.
    Keywords:  Biomarker; Endometrial cancer; RNA modification; m6A
    DOI:  https://doi.org/10.1007/s00432-022-04083-1
  2. Front Endocrinol (Lausanne). 2022 ;13 857765
    FTO Prevents Thyroid Cancer Progression by SLC7A11 m6A Methylation in a Ferroptosis-Dependent Manner.
    Fei-Hong Ji, Xing-Hao Fu, Guo-Quan Li, Qi He, Xin-Guang Qiu.
      N6 methyladenosine (m6A) modification serves as a novel epigenetic regulatory mechanism that is heavily implicated in the heredity of tumors. Meanwhile, fat mass and obesity-associated protein (FTO) has the potential to affect the regulation of m6A modification in the mRNA of key oncogenes as well as tumor suppressor genes that facilitate tumor progression. In our study, FTO was downregulated in papillary thyroid carcinoma (PTC) tissues. The role of FTO in PTC was assessed by Cell Counting Kit-8 analysis, cell scratch, migration, invasion experiment, flow cytometry apoptosis analysis, and nude mouse experiment. In addition to RNA-Seq and meRIP-Seq, luciferase reporting and mutation analysis have also identified SLC7A11 as the potential FTO regulatory gene. Moreover, X-ray electron microscopy, glutathione (GSH)/oxidized GSH, GPX, malondialdehyde determination, and western blot helped confirmed that FTO inhibited the development of PTC by downregulating the expression of SLC7A11 through ferroptosis. Finally, a rescue experiment was employed to clarify the relationship between FTO and its specific target gene SLC7A11. FTO is able to inhibit the occurrence of PTC by downregulating SLC7A11 in m6A independently, and it functions as a tumor suppressor gene in PTC. These findings could contribute to our understanding of the tumor malignancy regulated by m6A and might lead to new insights for potential biomarkers and therapeutic targets for the treatment of thyroid papillary carcinoma.
    Keywords:  FTO; SLC7A11; ferroptosis; m6A; papillary thyroid carcinoma
    DOI:  https://doi.org/10.3389/fendo.2022.857765
  3. Cancer Commun (Lond). 2022 Jun 21.
    Gene amplification-driven RNA methyltransferase KIAA1429 promotes tumorigenesis by regulating BTG2 via m6A-YTHDF2-dependent in lung adenocarcinoma.
    Chang Zhang, Qi Sun, Xu Zhang, Na Qin, Zhening Pu, Yayun Gu, Caiwang Yan, Meng Zhu, Juncheng Dai, Cheng Wang, Ni Li, Guangfu Jin, Hongxia Ma, Zhibin Hu, Erbao Zhang, Fengwei Tan, Hongbing Shen.
       BACKGROUND: Epigenetic alterations have been shown to contribute immensely to human carcinogenesis. Dynamic and reversible N6-methyladenosine (m6A) RNA modification regulates gene expression and cell fate. However, the reasons for activation of KIAA1429 (also known as VIRMA, an RNA methyltransferase) and its underlying mechanism in lung adenocarcinoma (LUAD) remain largely unexplored. In this study, we aimed to clarify the oncogenic role of KIAA1429 in the tumorigenesis of LUAD.
    METHODS: Whole-genome sequencing and transcriptome sequencing of LUAD data were used to analyze the gene amplification of RNA methyltransferase. The in vitro and in vivo functions of KIAA1429 were investigated. Transcriptome sequencing, methylated RNA immunoprecipitation sequencing (MeRIP-seq), m6A dot blot assays and RNA immunoprecipitation (RIP) were performed to confirm the modified gene mediated by KIAA1429. RNA stability assays were used to detect the half-life of the target gene.
    RESULTS: Copy number amplification drove higher expression of KIAA1429 in LUAD, which was correlated with poor overall survival. Manipulating the expression of KIAA1429 could regulate the proliferation and metastasis of LUAD. Mechanistically, the target genes of KIAA1429-mediated m6A modification were confirmed by transcriptome sequencing and MeRIP-seq assays. We also revealed that KIAA1429 could regulate BTG2 expression in an m6A-dependent manner. Knockdown of KIAA1429 significantly decreased the m6A levels of BTG2 mRNA, leading to enhanced YTH m6A RNA binding protein 2 (YTHDF2, the m6A "reader")-dependent BTG2 mRNA stability and promoted the expression of BTG2; thus, participating in the tumorigenesis of LUAD.
    CONCLUSIONS: Our data revealed the activation mechanism and important role of KIAA1429 in LUAD tumorigenesis, which may provide a novel view on the targeted molecular therapy of LUAD.
    Keywords:  BTG2; KIAA1429; LUAD; N6-methyladenosine; RNA methyltransferase; YTHDF2; gene amplification; mRNA stability
    DOI:  https://doi.org/10.1002/cac2.12325
  4. Int J Mol Sci. 2022 Jun 09. pii: 6451. [Epub ahead of print]23(12):
    The m6A Methyltransferase METTL3-Mediated N6-Methyladenosine Modification of DEK mRNA to Promote Gastric Cancer Cell Growth and Metastasis.
    Hui-Min Zhang, Fei-Fei Qi, Jun Wang, Yuan-Yuan Duan, Li-Li Zhao, Yun-Dan Wang, Tong-Cun Zhang, Xing-Hua Liao.
      Gastric cancer (GC) is the fifth most common cancer and the third deadliest cancer in the world, and the occurrence and development of GC are influenced by epigenetics. Methyltransferase-like 3 (METTL3) is a prominent RNA n6-adenosine methyltransferase (m6A) that plays an important role in tumor growth by controlling the work of RNA. This study aimed to reveal the biological function and molecular mechanism of METTL3 in GC. The expression level of METTL3 in GC tissues and cells was detected by qPCR, Western blot and immunohistochemistry, and the expression level and prognosis of METTL3 were predicted in public databases. CCK-8, colony formation, transwell and wound healing assays were used to study the effect of METTL3 on GC cell proliferation and migration. In addition, the enrichment effect of METTL3 on DEK mRNA was detected by the RIP experiment, the m6A modification effect of METTL3 on DEK was verified by the MeRIP experiment and the mRNA half-life of DEK when METTL3 was overexpressed was detected. The dot blot assay detects m6A modification at the mRNA level. The effect of METTL3 on cell migration ability in vivo was examined by tail vein injection of luciferase-labeled cells. The experimental results showed that METTL3 was highly expressed in GC tissues and cells, and the high expression of METTL3 was associated with a poor prognosis. In addition, the m6A modification level of mRNA was higher in GC tissues and GC cell lines. Overexpression of METTL3 in MGC80-3 cells and AGS promoted cell proliferation and migration, while the knockdown of METTL3 inhibited cell proliferation and migration. The results of in vitro rescue experiments showed that the knockdown of DEK reversed the promoting effects of METTL3 on cell proliferation and migration. In vivo experiments showed that the knockdown of DEK reversed the increase in lung metastases caused by the overexpression of METTL3 in mice. Mechanistically, the results of the RIP experiment showed that METTL3 could enrich DEK mRNA, and the results of the MePIP and RNA half-life experiments indicated that METTL3 binds to the 3'UTR of DEK, participates in the m6A modification of DEK and promotes the stability of DEK mRNA. Ultimately, we concluded that METTL3 promotes GC cell proliferation and migration by stabilizing DEK mRNA expression. Therefore, METTL3 is a potential biomarker for GC prognosis and a therapeutic target.
    Keywords:  DEK; METTL3; cell migration; cell proliferation; gastric cancer (GC); m6A methylation modification
    DOI:  https://doi.org/10.3390/ijms23126451
  5. Cancer Sci. 2022 Jun 22.
    M6 A Demethylase FTO Regulates Cisplatin Resistance of Gastric Cancer by Modulating Autophagy Activation via ULK1.
    Yan Zhang, Ling-Xi Gao, Wen Wang, Teng Zhang, Fang-Yi Dong, Wen-Ping Ding.
      Drug resistance is an important factor for treatment failure of gastric cancer. N6 -methyladenosine (m6 A) is the predominant mRNA internal modification in eukaryotes. The roles of m6 A modification in drug resistance of gastric cancer remains unclear. In the present study, the m6 A methylated RNA level was significantly decreased while the expression of m6 A demethylase fat mass and obesity-associated protein (FTO) was obviously elevated in the cisplatin-resistant (SGC-7901/DDP) gastric cancer cells. Knockdown of FTO reversed cisplatin resistance of SGC-7901/DDP cells both in vitro and in vivo, which were attributed to the inhibition of Unc-51-like kinase 1 (ULK1) mediated-autophagy. Mechanistically, ULK1 expression was regulated in the FTO-m6 A dependent and YTHDF2-mediated manner. Collectively, our findings demonstrate that the FTO/ULK1 axis exerts crucial roles in cisplatin resistance of gastric cancer.
    Keywords:  Autophagy; Cisplatin resistance; FTO; Gastric cancer; ULK1
    DOI:  https://doi.org/10.1111/cas.15469
  6. J Immunol Res. 2022 ;2022 6130806
    HIF-1α Regulated WTAP Overexpression Promoting the Warburg Effect of Ovarian Cancer by m6A-Dependent Manner.
    Yuanyuan Lyu, Yilin Zhang, Yuhan Wang, Yonghong Luo, Huafeng Ding, Peiling Li, Guantai Ni.
      N6-methyladenosine (m6A) RNA methylation has been determined to execute crucial functions in tumorigenesis and cancer development. WT1-associated protein (WTAP) has an important "writer" role in m6A modification, and it is also a nuclear protein that colocalizes with splicing factors and plays a critical role in cell function and cancer progression. However, little is known about the role of WTAP in ovarian cancer (OC) and its mechanisms. In this study, we found for the first time that hypoxia-inducible factor (HIF)-1α could positively regulate increased expression of WTAP under hypoxia. And further results revealed that WTAP expression was closely associated with the clinicopathological features of OC, and high expression of WTAP predicted low survival rate in patients with OC. In addition, cell proliferation and invasive capacity were significantly reduced after knockdown of WTAP expression in OC cells. However, cell proliferation and invasive ability were significantly enhanced after overexpression of WTAP. Additionally, we find that WTAP interacts with DGCR8 (a crucial chip protein) to regulate the expression of microRNA-200 (miR-200) in an m6A-dependent way. Further experiments showed that the key glycolysis enzyme HK2 could be positively regulated by miR-200, which significantly affected the intracellular Warburg effect. In conclusion, this is considered uncovered that upregulation of WTAP expression by HIF-1α intercedes with miRNA processing, accelerates the Warburg impact, and advances the event and advancement of tumor, thus giving a novel viewpoint on m6A adjustment in OC movement.
    DOI:  https://doi.org/10.1155/2022/6130806
  7. Clin Transl Med. 2022 Jun;12(6): e942
    FTO-mediated m6 A modification of SOCS1 mRNA promotes the progression of diabetic kidney disease.
    Qiang Sun, Houfa Geng, Meng Zhao, Yang Li, Xi Chen, Qian Sha, Peng Lai, Daoquan Tang, Dongzhi Yang, Jun Liang, Mengzhe Guo.
      
    Keywords:  diabetic kidney disease; m6A modification; single-cell omics
    DOI:  https://doi.org/10.1002/ctm2.942
  8. Front Cell Dev Biol. 2022 ;10 915685
    The Methylation Game: Epigenetic and Epitranscriptomic Dynamics of 5-Methylcytosine.
    Adele Alagia, Monika Gullerova.
      DNA and RNA methylation dynamics have been linked to a variety of cellular processes such as development, differentiation, and the maintenance of genome integrity. The correct deposition and removal of methylated cytosine and its oxidized analogues is pivotal for cellular homeostasis, rapid responses to exogenous stimuli, and regulated gene expression. Uncoordinated expression of DNA/RNA methyltransferases and demethylase enzymes has been linked to genome instability and consequently to cancer progression. Furthermore, accumulating evidence indicates that post-transcriptional DNA/RNA modifications are important features in DNA/RNA function, regulating the timely recruitment of modification-specific reader proteins. Understanding the biological processes that lead to tumorigenesis or somatic reprogramming has attracted a lot of attention from the scientific community. This work has revealed extensive crosstalk between epigenetic and epitranscriptomic pathways, adding a new layer of complexity to our understanding of cellular programming and responses to environmental cues. One of the key modifications, m5C, has been identified as a contributor to regulation of the DNA damage response (DDR). However, the various mechanisms of dynamic m5C deposition and removal, and the role m5C plays within the cell, remains to be fully understood.
    Keywords:  DNA; DNA damage; RNA; cancer; demethylases; hm5C; m5C; methyltransferases
    DOI:  https://doi.org/10.3389/fcell.2022.915685
  9. Sci Rep. 2022 Jun 18. 12(1): 10278
    RNA modification patterns based on major RNA modifications define tumor microenvironment characteristics in glioblastoma.
    Ganglei Li, Yu Zhu, Jun Gu, Tiesong Zhang, Feng Wang, Kaiyuan Huang, Chenjie Gu, Kangli Xu, Renya Zhan, Jian Shen.
      RNA modifications play a major role in tumorigenicity and progression, but the expression and function in glioblastoma (GBM) have not been well described. In this study, we developed a GBM score based on the differentially expressed genes (DEGs) between groups showing RNA modification patterns. We assessed the association between the GBM score and tumor microenvironment (TME) characteristics. Based on the gene expression of these regulators, we identified two clusters with distinct RNA modification patterns. Kaplan-Meier survival curves showed that patients in cluster 1 had worse survival than those in cluster 2. Kaplan-Meier and multivariate Cox regression analyses showed that GBM scores (based on DEGs between RNA modification patterns) are an independent predictive biomarker for patient prognosis. Besides, we found that samples with high scores were significantly associated with epithelial-to-mesenchymal transition and immune checkpoints, while samples with low scores were associated with cell cycle regulation. Importantly, GBM-score markedly positively correlated drug resistance, while negatively correlated with drug sensitive. The responders of anti-PD-1/PD-L1 immunotherapy tend to have a lower GBM score than non-responders. In conclusion, our comprehensive analysis of multiple RNA modifications in GBM revealed that RNA modification regulators were closely correlated with TME.
    DOI:  https://doi.org/10.1038/s41598-022-14539-6
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