bims-rimeca Biomed News
on RNA methylation in cancer
Issue of 2020‒10‒25
eight papers selected by
Sk Ramiz Islam
Saha Institute of Nuclear Physics


  1. Front Med (Lausanne). 2020 ;7 556
    Zhang L, Qiao Y, Huang J, Wan D, Zhou L, Lin S, Zheng S.
      As the most prevalent type of mRNA modification in mammals, N6-methyladenosine (m6A) is involved in various biological processes. Accumulating studies have indicated that the deregulation of m6A RNA modification is linked to cancer and other diseases. However, its implications in hepatocellular carcinoma (HCC) remain poorly characterized. Herein, we sought to investigate the expression pattern of 13 key regulators for m6A RNA modification and to evaluate their prognostic value in HCC. First, we systematically analyzed data from The Cancer Genome Atlas (TCGA) database pertaining to patient clinical information and mRNA gene expression data. We found that 11 out of 13 key regulators for m6A RNA modification showed significantly higher expression levels in HCC. Subsequently, we identified two subgroups (clusters 1 and 2) via consensus clustering based on the expression of 13 m6A RNA methylation regulators. Cluster 2 had a worse prognosis and was also significantly correlated with higher histological grade and pathological stage when compared with cluster 1. Moreover, cluster 2 was remarkedly enriched for cancer-related pathways. We further constructed a robust risk signature of five regulators for m6A RNA modification. Further analysis indicated that this risk signature could be an independent prognostic factor for HCC, and the prognostic relevance of this five-gene risk signature was successfully validated using the Gene Expression Omnibus (GEO) dataset. Finally, we established a novel prognostic nomogram on the basis of age, gender, histological grade, pathological stage, and risk score to precisely predict the prognosis of patients with HCC. In summary, we herein uncovered the vital role of regulators for m6A RNA modification in HCC and developed a risk signature as a promising prognostic marker in HCC patients.
    Keywords:  bioinformatics; hepatocellular carcinoma; m6A; nomogram; prognostic signature
    DOI:  https://doi.org/10.3389/fmed.2020.00556
  2. DNA Cell Biol. 2020 Oct 20.
    Fang J, Hu M, Sun Y, Zhou S, Li H.
      N6-Methyladenosine (m6A) refers to the methylation modification occurring at the nitrogen-6 position of adenosine. Many human physiological processes such as modulation of spermatogenesis are caused by m6A RNA modifications. However, the relationship between m6A RNA methylation regulators and kidney renal clear cell carcinoma (KIRC) remains rarely investigated. This work aimed to explore the influence of m6A RNA methylation regulators in KIRC. We examined abnormally expressed m6A RNA methylation regulators among different clinicopathological features of KIRC. We recognized three subgroups (KIRC1, KIRC2, and KIRC3) with significant differences in overall survival through consensus clustering of m6A RNA methylation regulators. Surprisingly, KIRC2 displayed elevated immune activity, but high proportions of immune-inhibitory cells (Tregs and myeloid-derived suppressor cell) based on single-sample gene set enrichment analysis (ssGSEA) and CIBERSORT analysis. Moreover, the KIRC2 subgroup had the lowest tumor mutation burden levels and the highest expression levels of 80% (12/15) of co-inhibitory molecules. Next, correlation analysis indicated that RBM15B expression was negatively correlated with multiple immune signatures, which was verified by ssGSEA and CIBERSORT analyses. Multiple immune-related and cancer-related pathways were enriched in the group with high RBM15B expression. Furthermore, a four-m6A RNA methylation regulator-based risk signature was constructed based on an ArrayExpress (E-MTAB-3267) dataset and confirmed in the The Cancer Genome Atlas (TCGA) testing cohort. In conclusion, our study successfully classified TCGA samples into three subgroups with different immune signatures, and suggested that the worse prognosis of KIRC2 is probably mediated by immune evasion. These findings will facilitate personalized immunotherapy in patients with KIRC. In addition, the risk score system was revealed as an independent prognostic marker that can predict survival in KIRC patients.
    Keywords:  N6-Methyladenosine; clear cell renal cell carcinoma; immune evasion; immune microenvironment; risk score signature
    DOI:  https://doi.org/10.1089/dna.2020.5767
  3. Front Cell Dev Biol. 2020 ;8 561703
    Xu Y, Liu J, Chen WJ, Ye QQ, Chen WT, Li CL, Wu HT.
      N6-methyladenosine (m6A) is one of the most common internal RNA modifications in eukaryotes. It is a dynamic and reversible process that requires an orchestrated participation of methyltransferase, demethylase, and methylated binding protein. m6A modification can affect RNA degradation, translation, and microRNA processing. m6A plays an important role in the regulation of various processes in living organisms. In addition to being involved in normal physiological processes such as sperm development, immunity, fat differentiation, cell development, and differentiation, it is also involved in tumor progression and stem cell differentiation. Curiously enough, cancer stem cells, a rare group of cells present in malignant tumors, retain the characteristics of stem cells and play an important role in the survival, proliferation, metastasis, and recurrence of cancers. Recently, studies demonstrated that m6A participates in the self-renewal and pluripotent regulation of these stem cells. However, considering that multiple targets of m6A are involved in different physiological processes, the exact role of m6A in cancer progression remains controversial. This article focuses on the mechanism of m6A and its effects on the differentiation of cancer stem cells, to provide a basis for elucidating the tumorigenesis mechanisms and exploring new potential therapeutic approaches.
    Keywords:  cancer; differentiation; hematopoietic; m6A; stem cell
    DOI:  https://doi.org/10.3389/fcell.2020.561703
  4. J Cell Mol Med. 2020 Oct 08.
    Zhang H, Zhang P, Long C, Ma X, Huang H, Kuang X, Du H, Tang H, Ling X, Ning J, Liu H, Deng X, Zou Y, Wang R, Cheng H, Lin S, Zhang Q, Yan J, Shen H.
      Retinoblastoma (RB) is a common intraocular malignancy in children. Due to the poor prognosis of RB, it is crucial to search for efficient diagnostic and therapeutic strategies. Studies have shown that methyltransferase-like 3 (METTL3), a major RNA N (6)-adenosine methyltransferase, is closely related to the initiation and development of cancers. Nevertheless, whether METTL3 is associated with RB remains unexplored. Therefore, we investigated the function and mechanisms of METTL3 in the regulation of RB progression. We manipulated METTL3 expression in RB cells. Then, cell proliferation, apoptosis, migration and invasion were analysed. We also analysed the expression of PI3K/AKT/mTOR pathway members. Finally, we incorporated subcutaneous xenograft mouse models into our studies. The results showed that METTL3 is highly expressed in RB patients and RB cells. We found that METTL3 knockdown decreases cell proliferation, migration and invasion of RB cells, while METTL3 overexpression promotes RB progression in vitro and in vivo. Moreover, two downstream members of the PI3K/AKT/mTOR pathway, P70S6K and 4EBP1, were affected by METTL3. Our study revealed that METTL3 promotes the progression of RB through PI3K/AKT/mTOR pathways in vitro and in vivo. Targeting the METTL3/PI3K/AKT/mTOR signalling axis could be a promising therapeutic strategy for the treatment of RB.
    Keywords:  METTL3; PI3K/AKT/mTOR; apoptosis; proliferation; retinoblastoma
    DOI:  https://doi.org/10.1111/jcmm.15736
  5. Cell Biol Int. 2020 Oct 20.
    Sun D, Zhao T, Zhang Q, Wu M, Zhang Z.
      As the first identified N6 -methyladenosine (m6 A) demethylase, fat mass and obesity-associated (FTO) protein is associated with fatty acid synthase (FASN) and lipid accumulation. However, little is known about the regulatory role of FTO in the expression of FASN and de novo lipogenesis through m6 A modification. In this study, we used FTO siRNA to explore the effects of FTO knockdown on hepatic lipogenesis and its underlying epigenetic mechanism in HepG2 cells. We found that knockdown of FTO increased m6 A levels in total RNA and enhanced the expression of YTH domain family member 2 (YTHDF2) which serves as the m6 A-binding protein. The de novo lipogenic enzymes and intracellular lipid content were significantly decreased under FTO knockdown. Mechanistically, knockdown of FTO dramatically enhanced m6 A levels in FASN mRNA, leading to the reduced expression of FASN mRNA through m6 A-mediated mRNA decay. The protein expressions of FASN along with acetyl CoA carboxylase (ACC) and ATP-citrate lyase (ACLY) were further decreased, which inhibited de novo lipogenesis, thereby resulting in the deficiency of lipid accumulation in HepG2 cells and the induction of cellular apoptosis. The results reveal that FTO regulates hepatic lipogenesis via FTO-dependent m6 A demethylation in FASN mRNA and indicate the critical role of FTO-mediated lipid metabolism in the survival of HepG2 cells. This study provides novel insights into a unique RNA epigenetic mechanism by which FTO mediates hepatic lipid accumulation through m6 A modification and indicates that FTO could be a potential target for obesity-related diseases and cancer. This article is protected by copyright. All rights reserved.
    Keywords:  FASN; FTO; YTHDF2; lipogenesis; m6A
    DOI:  https://doi.org/10.1002/cbin.11490
  6. Biochem Pharmacol. 2020 Oct 14. pii: S0006-2952(20)30520-7. [Epub ahead of print] 114284
    Li H, Zhang Y, Guo Y, Liu R, Yu Q, Gong L, Liu Z, Xie W, Wang C.
      Lung cancer has surpassed breast cancer as the leading cause of cancer death in females in developed countries and the leading cause of cancer death in males. Despite extensive research on lung cancer, the pathogenesis of lung cancer is not fully understood. ALKBH1 is a 2-oxoglutarate and Fe (II)-dependent dioxygenase responsible for the demethylation of 6-methyladenine (m6A) in RNA and is essential to multiple cellular processes in human. Numerous recent studies suggested that ALKBH1 played a role in tumorigenesis and tumor progression, but the role of ALKBH1 in lung cancer is largely unknown. In this study, we demonstrated that the expression levels of ALKBH1 in lung cancer tissues and cells were up regulated. The invasion and migration abilities of lung cancer cells were significantly suppressed in vitro upon the silencing of ALKBH1 while they were significantly promoted upon its overexpression. We next characterized the enzyme biochemically by analyzing the contribution of essential residues Y184, H231, D233, H287, R338, and R344 to its m6A demethylation activity. Lastly, our 3.1-Å crystal structure of mouse ALKBH1 revealed that the N-terminal domain of the protein forms close contacts with the core catalytic domain and might be responsible for the recognition of nucleic acid substrates. In summary, our combined cellular, biochemical, and structural results provide insight into the potential ALKBH1-based drug design for cancer therapies.
    Keywords:  ALKBH1; crystal structure; dioxygenase; lung cancer; m6A
    DOI:  https://doi.org/10.1016/j.bcp.2020.114284
  7. Exp Ther Med. 2020 Dec;20(6): 138
    Hu W, Liu W, Liang H, Zhang C, Zou M, Zou B.
      Methyltransferase-like 3 (METTL3) is a methyltransferase responsible for N6-methyladenosine mRNA modifications, which has been demonstrated to serve oncogenic roles in various types of cancer; however, the exact function of METTL3 in oesophageal squamous cell carcinoma (ESCC) has not been determined. The present study aimed to explore the regulatory role of METTL3 in ESCC. In the present study, reverse transcription-quantitative PCR and western blotting were used to examine mRNA and protein expression, CCK-8 assays and flow cytometry were used to determine cellular viability and apoptosis, and wound healing and Transwell assays were conducted to study cellular migration and invasion. The expression levels of METTL3 were significantly higher in ESCC tissues and cell lines compared with adjacent non-tumour tissues and the normal oesophageal epithelial cell line HET-1A, respectively. Increased METTL3 expression was associated with an advanced clinical stage of ESCC and poorer prognosis. Furthermore, the genetic knockdown of METTL3 using small interfering RNA significantly suppressed ESCC growth, invasion and migration in vitro, and induced cellular apoptosis, in addition to reducing the phosphorylation levels of PI3K and AKT. In conclusion, the present study demonstrated that the upregulation of METTL3 promoted ESCC progression, and that inhibition of METTL3 significantly suppressed the malignant phenotypes of ESCC cells, at least in part, by downregulating PI3K/AKT signalling activity. Thus, it is suggested that METTL3 may be a promising therapeutic target for ESCC.
    Keywords:  methyltransferase-like 3; oesophageal squamous cell carcinoma; oncogene
    DOI:  https://doi.org/10.3892/etm.2020.9267
  8. Trends Cell Biol. 2020 Oct 19. pii: S0962-8924(20)30190-2. [Epub ahead of print]
    Baksh SC, Finley LWS.
      Cell fate determination requires faithful execution of gene expression programs, which are increasingly recognized to respond to metabolic inputs. In particular, the family of α-ketoglutarate (αKG)-dependent dioxygenases, which include several chromatin-modifying enzymes, are emerging as key mediators of metabolic control of cell fate. αKG-dependent dioxygenases consume the metabolite αKG (also known as 2-oxoglutarate) as an obligate cosubstrate and are inhibited by succinate, fumarate, and 2-hydroxyglutarate. Here, we review the role of these metabolites in the control of dioxygenase activity and cell fate programs. We discuss the biochemical and transcriptional mechanisms enabling these metabolites to control cell fate and review evidence that nutrient availability shapes tissue-specific fate programs via αKG-dependent dioxygenases.
    Keywords:  2-hydroxyglutarate; alpha-ketoglutarate; cell fate; chromatin modifications; succinate; αKG-dependent dioxygenases
    DOI:  https://doi.org/10.1016/j.tcb.2020.09.010