bims-rimeca 2021-05-09 papers

bims-rimeca

Biomed News

on RNA methylation in cancer

Issue of 2021–05–09
ten papers selected by
Sk Ramiz Islam, Saha Institute of Nuclear Physics

Bioinformatic analyses and experimental validation of the role of m6A RNA methylation regulators in progression and prognosis of adrenocortical carcinoma.
METTL3 enhances the stability of MALAT1 with the assistance of HuR via m6A modification and activates NF-κB to promote the malignant progression of IDH-wildtype glioma.
mRNA modifications in cardiovascular biology and disease: with a focus on m6A modification.
Regulation of Ribosome Function by RNA Modifications in Hematopoietic Development and Leukemia: It Is Not Only a Matter of m6A.
N6-methyladenosine demethylase FTO impairs hepatic ischemia-reperfusion injury via inhibiting Drp1-mediated mitochondrial fragmentation.
Potential role of m6A RNA methylation regulators in osteosarcoma and its clinical prognostic value.
YTHDF2 is a potential target of AML1/ETO-HIF1α loop-mediated cell proliferation in t(8;21) AML.
Binding of RNA m6A by IGF2BP3 triggers chemoresistance of HCT8 cells via upregulation of ABCB1.
N6 -methyladenosine Steers RNA Metabolism and Regulation in Cancer.
METTL3 regulates viral m6A RNA modification and host cell innate immune responses during SARS-CoV-2 infection.

Aging (Albany NY). 2021 Apr 21. 13(8): 11919-11941

Bioinformatic analyses and experimental validation of the role of m6A RNA methylation regulators in progression and prognosis of adrenocortical carcinoma.

Fangshi Xu, Yibing Guan, Yubo Ma, Li Xue, Peng Zhang, Xiaojie Yang, Tie Chong.

  M6A-related genes have been proven to play an important role in many cancers. However, the role of that in adrenocortical carcinoma (ACC) has not been fully elucidated. In the present study, 77 ACC samples from TCGA database were divided into localized (n = 46) and metastatic (n = 31) groups. Three differential expression genes (DEGs) and five prognostic m6A genes were screened out. M6A-related risk signature (RBM15 and HNRNPC) was constructed by the Lasso regression analysis. In TCGA cohort (training cohort), the risk signature was identified as an ACC-independent prognostic factor and can distinguish the prognostic difference of ACC patients with clinical stage I-II, T3-4 and N0 stages. A nomogram combining T stage and m6A risk score was constructed to predict the overall survival rate (OSR) of individual at 1,2,3 year. Meanwhile, its prognostic value was also confirmed in the validation cohort (GSE33371 dataset). The potential associations between m6A risk level and immune checkpoint inhibitors (ICIs) therapy were also investigated via the TISIDB online tool. High m6A risk not only can suppress immunotherapy-related biological processes, but also repress the expressions of immune-checkpoint markers. Moreover, five pairs of clinical specimens were collected to confirm the overexpression of HNRNPC and non-ectopic expression of RBM15 in tumor tissues. HNRNPC was proven to promote the proliferation, migration and invasion of H295R and SW13 cells through MTT and Transwell assays. In conclusion, the m6A-related risk signature was beneficial for prognostic analysis and can affect immune microenvironment in ACC. HNRNPC played a pro-cancer role in ACC progression.

Keywords:  N6-methyladenosine; adrenocortical carcinoma; methylation; prognosis; risk signature

DOI:  https://doi.org/10.18632/aging.202896
Cancer Lett. 2021 Apr 29. pii: S0304-3835(21)00180-4. [Epub ahead of print]511 36-46

METTL3 enhances the stability of MALAT1 with the assistance of HuR via m6A modification and activates NF-κB to promote the malignant progression of IDH-wildtype glioma.

Yu-Zhou Chang, Rui-Chao Chai, Bo Pang, Xin Chang, Song Yuan An, Ke-Nan Zhang, Tao Jiang, Yong-Zhi Wang.

  Understanding the role of N6-methyladenosine (m6A) in tumorigenesis and stem cell maintenance is an emerging field in glioma research. However, it is necessary to study the function of m6A in IDH-mutation and IDH-wildtype gliomas separately. Here, we aimed to elucidate the role and mechanism of the m6A writer METTL3 in regulating the malignant progression of IDH-wildtype gliomas. We demonstrated that METTL3 expression is positively associated with a higher malignant grade and poorer prognosis of IDH-wildtype gliomas but not IDH-mutant gliomas. METTL3 could also promote the malignant progression of gliomas in both in vitro and in vivo models. Mechanistically, METTL3 upregulated MALAT1 expression by enhancing its stability via m6A modification. We further revealed that HuR was essential for METTL3-mediated MALAT1 stabilization, and upregulated MALAT1 subsequently activated NF-κB. Taken together, our findings confirmed that METTL3 promoted the malignant progression of IDH-wildtype gliomas and revealed important insight into the upstream regulatory mechanism of MALAT1 and NF-κB with a primary focus on m6A modification.

Keywords:  Glioma; LncRNA; METTL3; NF-κB; RNA modification

DOI:  https://doi.org/10.1016/j.canlet.2021.04.020
Cardiovasc Res. 2021 May 06. pii: cvab160. [Epub ahead of print]

mRNA modifications in cardiovascular biology and disease: with a focus on m6A modification.

Rajesh Kumari, Prabhat Ranjan, Zainab Gbongbo Suleiman, Sumanta Kumar Goswami, Jing Li, Ram Prasad, Suresh Kumar Verma.

  Among several known RNA modifications, N6-methyladenosine (m6A) is the most studied RNA epitranscriptomic modification and controls multiple cellular functions during development, differentiation, and disease. Current research advancements have made it possible to examine the regulatory mechanisms associated with RNA methylation and reveal its functional consequences in the pathobiology of many diseases, including heart failure. m6A methylation has been described both on coding (mRNA) and non-coding RNA species including rRNA, tRNA, small nuclear RNA and circular RNAs. The protein components which catalyze the m6A methylation are termed methyltransferase or "m6A writers." The family of proteins that recognize this methylation are termed "m6A readers" and finally the enzymes involved in the removal of a methyl group from RNA are known as demethylases or "m6A erasers." At the cellular level, different components of methylation machinery are tightly regulated by many factors to maintain the m6A methylation dynamics. The m6A methylation process impacts different stages of mRNA metabolism and the biogenesis of long non-coding RNA and miRNA. Although, mRNA methylation was initially described in the 1970s, its regulatory roles in various diseases, including cardiovascular diseases are broadly unexplored. Recent investigations suggest the important role of m6A mRNA methylation in both hypertrophic and ischemic heart diseases. In the present review, we evaluate the significance of m6A methylation in the cardiovascular system, in cardiac homeostasis and disease, all of which may help to improve therapeutic intervention for the treatment of heart failure.

Keywords:  Cardiovascular diseases; RNA demethylase; RNA methyltransferase; RNA modifications; m6A mRNA methylation

DOI:  https://doi.org/10.1093/cvr/cvab160
Int J Mol Sci. 2021 Apr 30. pii: 4755. [Epub ahead of print]22(9):

Regulation of Ribosome Function by RNA Modifications in Hematopoietic Development and Leukemia: It Is Not Only a Matter of m6A.

Francesco Fazi, Alessandro Fatica.

  Growth and maturation of hematopoietic stem cells (HSCs) are largely controlled at both transcriptional and post-transcriptional levels. In particular, hematopoietic development requires a tight control of protein synthesis. Furthermore, translational deregulation strongly contributes to hematopoietic malignancies. Researchers have recently identified a new layer of gene expression regulation that consists of chemical modification of RNA species, which led to the birth of the epitranscriptomics field. RNA modifications provide an additional level of control in hematopoietic development by acting as post-transcriptional regulators of lineage-specific genetic programs. Other reviews have already described the important role of the N6-methylation of adenosine (m6A) within mRNA species in regulating hematopoietic differentiation and diseases. The aim of this review is to summarize the current status of the role of RNA modifications in the regulation of ribosome function, beyond m6A. In particular, we discuss the importance of RNA modifications in tRNA and rRNA molecules. By balancing translational rate and fidelity, they play an important role in regulating normal and malignant hematopoietic development.

Keywords:  RNA modifications; epitranscriptomics; rRNA; tRNA

DOI:  https://doi.org/10.3390/ijms22094755
Cell Death Dis. 2021 May 04. 12(5): 442

N6-methyladenosine demethylase FTO impairs hepatic ischemia-reperfusion injury via inhibiting Drp1-mediated mitochondrial fragmentation.

Ying Dong Du, Wen Yuan Guo, Cong Hui Han, Ying Wang, Xiao Song Chen, Da Wei Li, Jin Long Liu, Ming Zhang, Nan Zhu, Xin Wang.

Despite N6-methyladenosine (m6A) is functionally important in various biological processes, its role and the underlying regulatory mechanism in the liver remain largely unexplored. In the present study, we showed that fat mass and obesity-associated protein (FTO, an m6A demethylase) was involved in mitochondrial function during hepatic ischemia-reperfusion injury (HIRI). We found that the expression of m6A demethylase FTO was decreased during HIRI. In contrast, the level of m6A methylated RNA was enhanced. Adeno-associated virus-mediated liver-specific overexpression of FTO (AAV8-TBG-FTO) ameliorated the HIRI, repressed the elevated level of m6A methylated RNA, and alleviated liver oxidative stress and mitochondrial fragmentation in vivo and in vitro. Moreover, dynamin-related protein 1 (Drp1) was a downstream target of FTO in the progression of HIRI. FTO contributed to the hepatic protective effect via demethylating the mRNA of Drp1 and impairing the Drp1-mediated mitochondrial fragmentation. Collectively, our findings demonstrated the functional importance of FTO-dependent hepatic m6A methylation during HIRI and provided valuable insights into the therapeutic mechanisms of FTO.

DOI: https://doi.org/10.1038/s41419-021-03622-x
J Orthop Surg Res. 2021 May 05. 16(1): 294

Potential role of m6A RNA methylation regulators in osteosarcoma and its clinical prognostic value.

Hua Liu, Guangzhen Qin, Yanan Ji, Xiaojian Wang, Hailin Bao, Xiaojun Guan, Aichun Wei, Zhigang Cai.

   BACKGROUND: Osteosarcoma is a disease with high mortality in children and adolescents, and metastasis is one of the important clinical features of osteosarcoma. N6-Methyladenosine (m6A) is the most abundant methylation modification in mRNA, which is regulated by m6A regulators. It is reported that it is related to the occurrence and development of tumors. However, the mechanism of its action in osteosarcoma is rarely known. The purpose of this study was to identify the potential role of m6A regulatory factor in osteosarcoma and its clinical prognostic value.
METHODS: Here, we used The Cancer Genome Atlas (TCGA) to comprehensively analyze the relationship between m6A regulatory factors and osteosarcoma (metastasis group and non-metastasis group). We analyzed their survival relationship and analyzed all the m6A regulatory factors in TCGA tumor data set by using the univariate Cox proportional hazard regression model. Finally, we selected two survival-related methylation regulators (FTO and IGF2BP2) as risk gene signature.
RESULTS: According to the median risk, patients were divided into low-risk group and high-risk group. Multivariate Cox regression analysis showed that these two risk genes were considered to be the key factors independently predicting the prognosis of patients with osteosarcoma. In addition, we verified their characteristics with gene expression omnibus (GEO) DataSets and confirmed that they are related to tumor and immune-related signaling pathways through gene set enrichment analysis (GESA) and immune infiltration analysis.
CONCLUSIONS: In conclusion, m6A regulators might play an important role in the metastasis of osteosarcoma and have potential important value for the prognosis and treatment strategy of osteosarcoma patients.

Keywords:  Osteosarcoma; Prognosis; TCGA; m6A; m6A regulators

DOI:  https://doi.org/10.1186/s13018-021-02422-5
Oncogene. 2021 May 06.

YTHDF2 is a potential target of AML1/ETO-HIF1α loop-mediated cell proliferation in t(8;21) AML.

Ze Chen, Yang-Liu Shao, Li-Li Wang, Ji Lin, Ji-Bin Zhang, Yi Ding, Bin-Bin Gao, Dai-Hong Liu, Xiao-Ning Gao.

The t(8;21) fusion product, AML1/ETO, and hypoxia-inducible factor 1α (HIF1α) form a feed-forward transcription loop that cooperatively transactivates the DNA methyltransferase 3a gene promoter that leads to DNA hypermethylation and drives leukemia cell growth. Suppression of the RNA N6-methyladenosine (m6A)-reader enzyme YTH N6-methyladenosine RNA binding protein 2 (YTHDF2) specifically compromises cancer stem cells in acute myeloid leukemia (AML) but promotes hematopoietic stem cell expansion without derailing normal hematopoiesis. However, the relevance of expression between AML1/ETO-HIF1α loop and YTHDF2, and its functional relationship with t(8;21) AML have not been documented. Here, we show that YTHDF2 is highly expressed in t(8;21) AML patients and associated with a higher risk of relapse and inferior relapse-free survival. Knockdown of YTHDF2 in leukemia cells causes an impaired cell proliferation rate in vitro and in mice. Mechanistically, HIF1α is able to bind to the hypoxia-response elements of the 5'-untranslated region of the YTHDF2 gene and promotes the transactivity of the YTHDF2 promoter. Knockdown and overexpression of either AML1/ETO or HIF1α resulted in decreased and increased YTHDF2 protein and mRNA expression in t(8;21) AML cells. In particular, knockdown of YTHDF2 resulted in increased global mRNA m6A levels in t(8;21) AML cells, accompanied by increased TNF receptor superfamily member 1b (TNFRSF1b) mRNA and protein expression levels. Last, we demonstrated that the m6A methylation and expression levels of the TNFRSF1b gene were both negatively correlated with HIF1α expression levels. In conclusion, YTHDF2 is a downstream target of the AML1/ETO-HIF1α loop and promotes cell proliferation probably by modulating the global m6A methylation in t(8;21) AML.

DOI: https://doi.org/10.1038/s41388-021-01818-1
Am J Cancer Res. 2021 ;11(4): 1428-1445

Binding of RNA m6A by IGF2BP3 triggers chemoresistance of HCT8 cells via upregulation of ABCB1.

Zhongmin Yang, Fangqing Zhao, Xiaofan Gu, Lixing Feng, Mingshi Xu, Tian Li, Xuan Liu, Xiongwen Zhang.

The overexpression of ATP-binding cassette transporters subfamily B member 1 (ABCB1) is known to be the primary trigger of multidrug resistance (MDR) in colorectal cancer (CRC), leading to chemotherapy failure. However, factors that regulate chemoresistance in CRC cells are largely unknown. To identify proteins involved in MDR in CRC, we used proteomics and transcriptomics approaches to analyze HCT8/T cells and parental HCT8 cells. Results showed that the expression of insulin-like growth factor-2 mRNA-binding protein 3 (IGF2BP3) was upregulated in HCT8/T cells, and siIGF2BP3 remarkably elevated the sensitivity of HCT8/T cells to DOX. Overexpression of IGF2BP3 promoted ABCB1 expression, and reduced the sensitivity to ABCB1 substrates. Conversely, knockdown of IGF2BP3 reduced ABCB1 expression, and increased the sensitivity to ABCB1 substrates in vitro and in vivo. This phenomeon was further confirmed by the strong association of IGF2BP3 and ABCB1 expression with DOX sensitivity. Mechanistically, IGF2BP3, as a N6-methyladenosine (m6A) reader, directly bound to the m6A-modified region of ABCB1 mRNA, thereby promoting the stability and expression of ABCB1 mRNA. Overall, the results showed that IGF2BP3 bound to the m6A modification region of ABCB1 mRNA, and conferred chemoresistance in CRC cells via upregulation of ABCB1. These findings suggest that IGF2BP3 might be a potential biomarker for predicting the development of MDR in CRC. Targeting IGF2BP3 might be an important chemotherapeutic strategy for preventing MDR development in CRC.

Keywords: ABCB1; Colorectal cancer; IGF2BP3; chemoresistance; m6A
Cancer Commun (Lond). 2021 May 06.

N6 -methyladenosine Steers RNA Metabolism and Regulation in Cancer.

Shenghua Dong, Yutong Wu, Yadi Liu, Hengyou Weng, Huilin Huang.

  As one of the most studied ribonucleic acid (RNA) modifications in eukaryotes, N6 -methyladenosine (m6 A) has been shown to play a predominant role in controlling gene expression and influence physiological and pathological processes such as oncogenesis and tumor progression. Writer and eraser proteins, acting opposite to deposit and remove m6 A epigenetic marks, respectively, shape the cellular m6 A landscape, while reader proteins preferentially recognize m6 A modifications and mediate fate decision of the methylated RNAs, including RNA synthesis, splicing, exportation, translation, and stability. Therefore, RNA metabolism in cells is greatly influenced by these three classes of m6 A regulators. Aberrant expression of m6 A regulators has been widely reported in various types of cancer, leading to cancer initiation, progression, and drug resistance. The close links between m6 A and cancer shed light on the potential use of m6 A methylation and its regulators as prognostic biomarkers and drug targets for cancer therapy. Given the notable effects of m6 A in reversing chemoresistance and enhancing immune therapy, it is a promising target for combined therapy. Herein, we summarize the recent discoveries on m6 A and its regulators, emphasizing their influences on RNA metabolism, their dysregulation and impacts in diverse malignancies, and discuss the clinical implications of m6 A modification in cancer.

Keywords:  RNA epigenetics; RNA metabolism; cancer therapy; chemoresistance; immunotherapy; m6A methylation; oncogenesis; prognostic biomarkers

DOI:  https://doi.org/10.1002/cac2.12161
Cell Rep. 2021 May 03. pii: S2211-1247(21)00425-3. [Epub ahead of print] 109091

METTL3 regulates viral m6A RNA modification and host cell innate immune responses during SARS-CoV-2 infection.

Na Li, Hui Hui, Bill Bray, Gwendolyn Michelle Gonzalez, Mark Zeller, Kristian G Anderson, Rob Knight, Davey Smith, Yinsheng Wang, Aaron F Carlin, Tariq M Rana.

  It is urgent and important to understand the relationship of the widespread severe acute respiratory syndrome coronavirus clade 2 (SARS-CoV-2) with host immune response and study the underlining molecular mechanism. N6-methylation of adenosine (m6A) in RNA regulates many physiological and disease processes. Here, we investigate m6A modification of the SARS-CoV-2 gene in regulating the host cell innate immune response. Our data show that the SARS-CoV-2 virus has m6A modifications that are enriched in the 3' end of the viral genome. We find that depletion of the host cell m6A methyltransferase METTL3 decreases m6A levels in SARS-CoV-2 and host genes, and m6A reduction in viral RNA increases RIG-I binding and subsequently enhances the downstream innate immune signaling pathway and inflammatory gene expression. METTL3 expression is reduced and inflammatory genes are induced in patients with severe coronavirus disease 2019 (COVID-19). These findings will aid in the understanding of COVID-19 pathogenesis and the design of future studies regulating innate immunity for COVID-19 treatment.

Keywords:  METTL3; RIG-I; SARS-CoV-2; host innate immunity; inflammation; m(6)A RNA modification

DOI:  https://doi.org/10.1016/j.celrep.2021.109091