bims-rimeca Biomed News
on RNA methylation in cancer
Issue of 2022–07–03
ten papers selected by
Sk Ramiz Islam, Saha Institute of Nuclear Physics
  1. Novel insights into roles of N6-methyladenosine reader YTHDF2 in cancer progression.
  2. METTL3-mediated m6A modification promotes processing and maturation of pri-miRNA-19a to facilitate nasopharyngeal carcinoma cell proliferation and invasion.
  3. N6-methyladenosine (m6A) reader IGF2BP2 stabilizes HK2 stability to accelerate the Warburg effect of oral squamous cell carcinoma progression.
  4. Methyltransferase-like 3 silenced inhibited the ferroptosis development via regulating the glutathione peroxidase 4 levels in the intracerebral hemorrhage progression.
  5. m6A demethylase ALKBH5 is required for antibacterial innate defense by intrinsic motivation of neutrophil migration.
  6. NSUN2-mediated RNA m5C modification modulates uveal melanoma cell proliferation and migration.
  7. N(6)-methyladenosine methylation-regulated polo-like kinase 1 cell cycle homeostasis as a potential target of radiotherapy in pancreatic adenocarcinoma.
  8. Mitochondrial RNA modifications shape metabolic plasticity in metastasis.
  9. Tumor-suppressive MEG3 induces microRNA-493-5p expression to reduce arabinocytosine chemoresistance of acute myeloid leukemia cells by downregulating the METTL3/MYC axis.
  10. CircEZH2/miR-133b/IGF2BP2 aggravates colorectal cancer progression via enhancing the stability of m6A-modified CREB1 mRNA.
  1. J Cancer Res Clin Oncol. 2022 Jun 28.
    Novel insights into roles of N6-methyladenosine reader YTHDF2 in cancer progression.
    Rui Liu, Yachun Jia, Guangyao Kong, Aili He.
      N6-methyladenosine (m6A) is the most abundant RNA modification. M6A RNA methylation is reversible: m6A is installed by "writers", removed by "erasers", and recognized by "readers". Readers are executors to regulate RNA metabolism by recognizing specific m6A sites, including RNA splicing, export, translation and decay. YTHDF2 is the first identified m6A reader protein. YTHDF2 interacts with m6A-containing transcripts to accelerate the degradation process and regulate various biological processes, such as viral infection, stem cell development and cancer progression. Although there are some reviews about m6A modification in physiological and pathological processes, few reviews focus on roles of YTHDF2 in cancers to date. Therefore, in this review, we attempted to systematically summarize m6A reader protein YTHDF2: its structure, mechanisms in regulating RNA metabolism, roles in cancer progression and potential application for cancer treatment, which might inspire new ideas for m6A research in cancers and provide novel insights into cancer treatment.
    Keywords:  Cancer progression; Cancer therapy; YTHDF2; m6A modification
    DOI:  https://doi.org/10.1007/s00432-022-04134-7
  2. Physiol Genomics. 2022 Jun 27.
    METTL3-mediated m6A modification promotes processing and maturation of pri-miRNA-19a to facilitate nasopharyngeal carcinoma cell proliferation and invasion.
    Xinggu Luo, Qingshan Jiang, Lijun Liu, Qingyun Liao, Jing Yu, Zheng Xiang, Yongqian Gong.
      The interplay between N6-methyladenosine (m6A) modification and microRNAs (miRs) participates in cancer progression. This study is conducted to explore the role of miR-19a-3p in nasopharyngeal carcinoma (NPC) cell proliferation and invasion. RT-qPCR and western blot showed that miR-19a-3p was upregulated in NPC tissues and cells and related to poor prognosis, methyltransferase-like 3 (METTL3) was highly expressed while BMP and activin membrane-bound inhibitor (BAMBI) was weakly expressed in NPC tissues and cells. miR-19a-3p downregulation inhibited cell proliferation and invasion while miR-19a-3p overexpression played an opposite role. m6A quantification and m6A RNA immunoprecipitation assays showed that METTL3-mediated m6A modification promoted the processing and maturation of pri-miR-19a via DGCR8. Dual-luciferase assay showed that BAMBI was a target of miR-19a-3p. The rescue experiments showed that BAMBI downregulation reversed the role of miR-19a-3p inhibition in NPC cells. A xenograft tumor model showed that METTL3 downregulation inhibited tumor growth via the miR-19a-3p/BAMBI in vivo. Overall, our findings elicited that METTL3-mediated m6A modification facilitated the processing and maturation of pri-miR-19a via DGCR8 to upregulate miR-19a-3p, and miR-19a-3p inhibited BAMBI expression to promote NPC cell proliferation and invasion, thus driving NPC progression.
    Keywords:  METTL3; Nasopharyngeal carcinoma; m6A modification; miR-19a-3p; pri-miRNA
    DOI:  https://doi.org/10.1152/physiolgenomics.00007.2022
  3. J Cancer Res Clin Oncol. 2022 Jun 28.
    N6-methyladenosine (m6A) reader IGF2BP2 stabilizes HK2 stability to accelerate the Warburg effect of oral squamous cell carcinoma progression.
    Ke Xu, Xiaojuan Dai, Jiankun Wu, Kai Wen.
       PURPOSE: The N6-methyladenosine (m6A) has been involved in the regulation of cell proliferation and metastasis in multiple cancers. However, the biological significance of m6A reader IGF2BP2 in oral squamous cell carcinoma (OSCC) and the mechanism of IGF2BP2 itself have not been fully investigated.
    METHODS: The cellular phenotypes of OSCC cells were determined by CCK-8 and transwell migration assays. The energy metabolism was detected using glucose uptake/lactate production assay and extracellular acidification rate analysis. The molecular interaction was tested by  RNA immunoprecipitation  assay.
    RESULTS: Here, results indicated that IGF2BP2 was up-regulated in OSCC and that it acted as a predictor of poor prognosis. IGF2BP2 promoted the proliferation, migration and Warburg effect of OSCC cells in vitro. Mechanistical assays illustrated that IGF2BP2 directly interacted with HK2 mRNA by binding the 3'-UTR m6A site. Moreover, IGF2BP2 positively promoted the stability of HK2 mRNA and thus the protein level of HK2 increased upon IGF2BP2 overexpression.
    CONCLUSIONS: In conclusion, the IGF2BP2/m6A/HK2 axis accelerated the abnormal energy metabolism of OSCC. Taken together, these findings revealed a novel mechanism by which IGF2BP2 functions in OSCC progression, which may provide new therapy options for OSCC patients.
    Keywords:  HK2; IGF2BP2; N6-methyladenosine; Oral squamous cell carcinoma; Warburg effect
    DOI:  https://doi.org/10.1007/s00432-022-04093-z
  4. Bioengineered. 2022 Jun;13(6): 14215-14226
    Methyltransferase-like 3 silenced inhibited the ferroptosis development via regulating the glutathione peroxidase 4 levels in the intracerebral hemorrhage progression.
    Liu Zhang, Xiangyu Wang, Wenqiang Che, Yongjun Yi, Shuoming Zhou, Yongjian Feng.
      This study examined the effects of methyltransferase-like 3 (METTL3) on ferroptosis during intracerebral hemorrhage (ICH) progression. The brain microvascular endothelial cells (BMVECs) were stimulated with oxygen and glucose deprivation (OGD) and hemin to establish an ICH model. Cell viability was tested using a CCK8 assay. The levels of Fe2+, glutathione, reactive oxygen species, LPO, and MDA were determined using the corresponding commercial kits. Cell death was analyzed using TUNEL and propidium iodide staining. The correlation between METTL3 and glutathione peroxidase 4 (GPX4) was analyzed using Spearman's correlation test and further confirmed using the CHIP assay. Western blotting and RT-qPCR were performed to measure the relative expression levels. Mice were injected with 0.2 units collagenase IV to establish an ICH model in vivo. We found that the Fe2+, reactive oxygen species, LPO, and MDA levels were enhanced, and glutathione was depleted in OGD/H-treated BMVECs as well as in ICH mice. Additionally, cell viability and SLC7A11 protein levels decreased, and cell death and TFR1 protein levels increased in OGD/H-treated BMVECs. METTL3 silencing relieves OGD/H-induced injury in BMVECs. In addition, METTL3 was significantly negatively related to GPX4, which was further confirmed by the CHIP assay. Silencing of METTL3 decreased the N6-methyladenosine levels of GPX4 and increased its mRNA levels of GPX4. GPX4 knockdown neutralized the role of METTL3 in OGD/H-treated BMVECs. These results implied that ferroptosis occurred in the ODG/H-treated BMVECs and ICH mouse models. METTL3 silencing effectively suppressed ferroptosis by regulating N6-methyladenosine and mRNA levels of GPX4.
    Keywords:  GPX4; Intracerebral hemorrhage; METTL3; ferroptosis
    DOI:  https://doi.org/10.1080/21655979.2022.2084494
  5. Signal Transduct Target Ther. 2022 Jun 29. 7(1): 194
    m6A demethylase ALKBH5 is required for antibacterial innate defense by intrinsic motivation of neutrophil migration.
    Yang Liu, Renjie Song, Lu Zhao, Zhike Lu, Yini Li, Xinyi Zhan, Fengjiao Lu, Jiang Yang, Yamei Niu, Xuetao Cao.
      Neutrophil migration into the site of infection is necessary for antibacterial innate defense, whereas impaired neutrophil migration may result in excessive inflammation and even sepsis. The neutrophil migration directed by extracellular signals such as chemokines has been extensively studied, yet the intrinsic mechanism for determining neutrophil ability to migrate needs further investigation. N6-methyladenosine (m6A) RNA modification is important in immunity and inflammation, and our preliminary data indicate downregulation of RNA m6A demethylase alkB homolog 5 (ALKBH5) in neutrophils during bacterial infection. Whether m6A modification and ALKBH5 might intrinsically modulate neutrophil innate response remain unknown. Here we report that ALKBH5 is required for antibacterial innate defense by enhancing intrinsic ability of neutrophil migration. We found that deficiency of ALKBH5 increased mortality of mice with polymicrobial sepsis induced by cecal ligation and puncture (CLP), and Alkbh5-deficient CLP mice exhibited higher bacterial burden and massive proinflammatory cytokine production in the peritoneal cavity and blood because of less neutrophil migration. Alkbh5-deficient neutrophils had lower CXCR2 expression, thus exhibiting impaired migration toward chemokine CXCL2. Mechanistically, ALKBH5-mediated m6A demethylation empowered neutrophils with high migration capability through altering the RNA decay, consequently regulating protein expression of its targets, neutrophil migration-related molecules, including increased expression of neutrophil migration-promoting CXCR2 and NLRP12, but decreased expression of neutrophil migration-suppressive PTGER4, TNC, and WNK1. Our findings reveal a previously unknown role of ALKBH5 in imprinting migration-promoting transcriptome signatures in neutrophils and intrinsically promoting neutrophil migration for antibacterial defense, highlighting the potential application of targeting neutrophil m6A modification in controlling bacterial infections.
    DOI:  https://doi.org/10.1038/s41392-022-01020-z
  6. Epigenetics. 2022 Jun 26. 1-12
    NSUN2-mediated RNA m5C modification modulates uveal melanoma cell proliferation and migration.
    Guangying Luo, Weiwei Xu, Xiaoyan Chen, Siqi Wang, Jiao Wang, Feng Dong, Dan-Ning Hu, Peter S Reinach, Dongsheng Yan.
      RNA 5-methylcytosine (m5C) is a widespread post-transcriptional modification involved in diverse biological processes through controlling RNA metabolism. However, its roles in uveal melanoma (UM) remain unknown. Here, we describe the biological roles and regulatory mechanisms of RNA m5C in UM. Initially, we identified significantly elevated global RNA m5C levels in both UM cells and tissue specimens using ELISA assay and dot blot analysis. Meanwhile, NOP2/Sun RNA methyltransferase family member 2 (NSUN2) was upregulated in both types of these samples, whereas NSUN2 knockdown significantly decreased RNA m5C level. Such declines inhibited UM cell migration and suppressed cell proliferation through cell cycle G1 arrest. Furthermore, bioinformatic analyses, m5C-RIP-qPCR, and luciferase assay identified β-Catenin (CTNNB1) as a direct target of NSUN2-mediated m5C modification in UM cells. Additionally, overexpression of miR-124a in UM cells diminished NSUN2 expression levels indicating that it is an upstream regulator of this response. Our study suggests that NSUN2-mediated RNA m5C methylation provides a potential novel target to improve the therapeutic management of UM pathogenesis.
    Keywords:  CTNNB1; NSUN2; RNA m5C; cell proliferation and migration; miR-124a; uveal melanoma
    DOI:  https://doi.org/10.1080/15592294.2022.2088047
  7. Sci Rep. 2022 Jun 30. 12(1): 11074
    N(6)-methyladenosine methylation-regulated polo-like kinase 1 cell cycle homeostasis as a potential target of radiotherapy in pancreatic adenocarcinoma.
    Shotaro Tatekawa, Keisuke Tamari, Ryota Chijimatsu, Masamitsu Konno, Daisuke Motooka, Suguru Mitsufuji, Hirofumi Akita, Shogo Kobayashi, Yoshiki Murakumo, Yuichiro Doki, Hidetoshi Eguchi, Hideshi Ishii, Kazuhiko Ogawa.
      In pancreatic cancer, methyltransferase-like 3 (METTL3), a N(6)-methyladenosine (m6A) methyltransferase, has a favorable effect on tumors and is a risk factor for patients' prognosis. However, the details of what genes are regulated by METTL3 remain unknown. Several RNAs are methylated, and what genes are favored in pancreatic cancer remains unclear. By epitranscriptomic analysis, we report that polo-like kinase 1 (PLK1) is an important hub gene defining patient prognosis in pancreatic cancer and that RNA methylation is involved in regulating its cell cycle-specific expression. We found that insulin like growth factor 2 mRNA binding protein 2 (IGF2BP2) binds to m6A of PLK1 3' untranslated region and is involved in upregulating PLK1 expression and that demethylation of this site activates the ataxia telangiectasia and Rad3-related protein pathway by replicating stress and increasing mitotic catastrophe, resulting in increased radiosensitivity. This suggests that PLK1 methylation is essential for cell cycle maintenance in pancreatic cancer and is a new therapeutic target.
    DOI:  https://doi.org/10.1038/s41598-022-15196-5
  8. Nature. 2022 Jun 29.
    Mitochondrial RNA modifications shape metabolic plasticity in metastasis.
    Sylvain Delaunay, Gloria Pascual, Bohai Feng, Kevin Klann, Mikaela Behm, Agnes Hotz-Wagenblatt, Karsten Richter, Karim Zaoui, Esther Herpel, Christian Münch, Sabine Dietmann, Jochen Hess, Salvador Aznar Benitah, Michaela Frye.
      Aggressive and metastatic cancers show enhanced metabolic plasticity1, but the precise underlying mechanisms of this remain unclear. Here we show how two NOP2/Sun RNA methyltransferase 3 (NSUN3)-dependent RNA modifications-5-methylcytosine (m5C) and its derivative 5-formylcytosine (f5C) (refs.2-4)-drive the translation of mitochondrial mRNA to power metastasis. Translation of mitochondrially encoded subunits of the oxidative phosphorylation complex depends on the formation of m5C at position 34 in mitochondrial tRNAMet. m5C-deficient human oral cancer cells exhibit increased levels of glycolysis and changes in their mitochondrial function that do not affect cell viability or primary tumour growth in vivo; however, metabolic plasticity is severely impaired as mitochondrial m5C-deficient tumours do not metastasize efficiently. We discovered that CD36-dependent non-dividing, metastasis-initiating tumour cells require mitochondrial m5C to activate invasion and dissemination. Moreover, a mitochondria-driven gene signature in patients with head and neck cancer is predictive for metastasis and disease progression. Finally, we confirm that this metabolic switch that allows the metastasis of tumour cells can be pharmacologically targeted through the inhibition of mitochondrial mRNA translation in vivo. Together, our results reveal that site-specific mitochondrial RNA modifications could be therapeutic targets to combat metastasis.
    DOI:  https://doi.org/10.1038/s41586-022-04898-5
  9. J Transl Med. 2022 Jun 27. 20(1): 288
    Tumor-suppressive MEG3 induces microRNA-493-5p expression to reduce arabinocytosine chemoresistance of acute myeloid leukemia cells by downregulating the METTL3/MYC axis.
    Airong Wang, Yufei Chen, Luyao Shi, Mengya Li, Lingling Li, Shujuan Wang, Chong Wang.
       BACKGROUND: Chemoresistance serves as a huge obstacle for acute myeloid leukemia (AML) patients. To counteract the chemoresistance in AML cells, we discussed the role of maternally expressed gene 3 (MEG3) in arabinocytosine (AraC) chemoresistance in AML cells.
    METHODS: MEG3, microRNA (miR)-493-5p, methyltransferase-like 3 (METTL3) and MYC expression in AML cells was determined and then their interactions were also analyzed. Then, the viability and apoptosis of AML cells were determined through loss- and gain- function assay. The level of m6A modification in AML cells was examined. AML mouse models were also established to validate the potential roles of MEG3.
    RESULTS: MEG3 and miR-493-5p were downregulated in AML cells, and they were lower in resistant cells than in parental cells. MEG3 led to elevated expression of miR-493-5p which targeted METTL3. METTL3 increased expression of MYC by promoting its m6A levels. Overexpression of MEG3 and miR-493-5p or knockdown of METTL3 inhibited HL-60 and Molm13 cell proliferation and promoted their apoptosis. Overexpressed MEG3 induced heightened sensitivity of AML cells to AraC. However, the suppression of miR-493-5p reversed the effects of overexpressed MEG3 on AML cells.
    CONCLUSIONS: Collectively, MEG3 could upregulate miR-493-5p expression and suppress the METTL3/MYC axis through MYC m6A methylation, by which MEG3 promoted the chemosensitivity of AML cells.
    Keywords:  Acute myeloid leukemia; Chemotherapy; Maternally expressed gene 3; Methyltransferase-like 3; microRNA-493-5p
    DOI:  https://doi.org/10.1186/s12967-022-03456-x
  10. Mol Cancer. 2022 Jun 30. 21(1): 140
    CircEZH2/miR-133b/IGF2BP2 aggravates colorectal cancer progression via enhancing the stability of m6A-modified CREB1 mRNA.
    Bing Yao, Qinglin Zhang, Zhou Yang, Fangmei An, He Nie, Hui Wang, Cheng Yang, Jing Sun, Ke Chen, Jingwan Zhou, Bing Bai, Shouyong Gu, Wei Zhao, Qiang Zhan.
       BACKGROUND: Aberrant expression of circular RNAs (circRNAs) contributes to the initiation and progression of human malignancies, but the underlying mechanisms remain largely elusive.
    METHODS: High-throughput sequencing was performed to screen aberrantly expressed circRNAs or miRNAs in colorectal cancer (CRC) and adjacent normal tissues. A series of gain- and loss-of-function studies were conducted to evaluate the biological behaviors of CRC cells. RNA pulldown, mass spectrometry, RIP, qRT-PCR, Western blot, luciferase reporter assays and MeRIP-seq analysis were further applied to dissect the detailed mechanisms.
    RESULTS: Here, a novel circRNA named circEZH2 (hsa_circ_0006357) was screened out by RNA-seq in CRC tissues, whose expression is closely related to the clinicpathological characteristics and prognosis of CRC patients. Biologically, circEZH2 facilitates the proliferation and migration of CRC cells in vitro and in vivo. Mechanistically, circEZH2 interacts with m6A reader IGF2BP2 and blocks its ubiquitination-dependent degradation. Meanwhile, circEZH2 could serve as a sponge of miR-133b, resulting in the upregulation of IGF2BP2. Particularly, circEZH2/IGF2BP2 enhances the stability of CREB1 mRNA, thus aggravating CRC progression.
    CONCLUSIONS: Our findings not only reveal the pivotal roles of circEZH2 in modulating CRC progression, but also advocate for attenuating circEZH2/miR-133b/IGF2BP2/ CREB1 regulatory axis to combat CRC.
    Keywords:  CREB1; CircEZH2; Colorectal cancer; IGF2BP2; miR-133b
    DOI:  https://doi.org/10.1186/s12943-022-01608-7
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