bims-rimeca Biomed News
on RNA methylation in cancer
Issue of 2022‒01‒23
fourteen papers selected by
Sk Ramiz Islam
Saha Institute of Nuclear Physics
  1. RNA demethylase ALKBH5 in cancer: from mechanisms to therapeutic potential.
  2. N6-methyladenosine demethylase FTO promotes growth and metastasis of gastric cancer via m6A modification of caveolin-1 and metabolic regulation of mitochondrial dynamics.
  3. The METTL5-TRMT112 N6-methyladenosine methyltransferase complex regulates mRNA translation via 18S rRNA methylation.
  4. METTL3 facilitates multiple myeloma tumorigenesis by enhancing YY1 stability and pri-microRNA-27 maturation in m6A-dependent manner.
  5. METTL14-mediated Lnc-LSG1 m6A modification inhibits clear cell renal cell carcinoma metastasis via regulating ESRP2 ubiquitination.
  6. Roles and drug development of METTL3 (methyltransferase-like 3) in anti-tumor therapy.
  7. Long intergenic non-protein coding RNA 1273 confers sorafenib resistance in hepatocellular carcinoma via regulation of methyltransferase 3.
  8. N6-Methyladenosine-Related lncRNAs as potential biomarkers for predicting prognoses and immune responses in patients with cervical cancer.
  9. RNA m6A methylation regulates the dissemination of cancer cells via modulating expression and membrane localization of β-catenin.
  10. Intermittent Fasting Improves High-Fat Diet-Induced Obesity Cardiomyopathy via Alleviating Lipid Deposition and Apoptosis and Decreasing m6A Methylation in the Heart.
  11. ZC3H13-mediated N6-methyladenosine modification of PHF10 is impaired by fisetin which inhibits the DNA damage response in pancreatic cancer.
  12. METTL3 facilitates the progression of hepatocellular carcinoma by modulating the m6A level of USP7.
  13. Dihydroartemisinin alleviates AngII-induced vascular smooth muscle cell proliferation and inflammatory response by blocking the FTO/NR4A3 axis.
  14. Downregulation of m6 A writer complex member METTL14 in bladder urothelial carcinoma suppresses tumor aggressiveness.
  1. J Hematol Oncol. 2022 Jan 21. 15(1): 8
    RNA demethylase ALKBH5 in cancer: from mechanisms to therapeutic potential.
    Jianwei Qu, Haimeng Yan, Yifan Hou, Wen Cao, Yang Liu, Enfan Zhang, Jingsong He, Zhen Cai.
      RNA demethylase ALKBH5 takes part in the modulation of N6-methyladenosine (m6A) modification and controls various cell processes. ALKBH5-mediated m6A demethylation regulates gene expression by affecting multiple events in RNA metabolism, e.g., pre-mRNA processing, mRNA decay and translation. Mounting evidence shows that ALKBH5 plays critical roles in a variety of human malignancies, mostly via post-transcriptional regulation of oncogenes or tumor suppressors in an m6A-dependent manner. Meanwhile, increasing non-coding RNAs are recognized as functional targets of ALKBH5 in cancers. Here we reviewed up-to-date findings about the pathological roles of ALKBH5 in cancer, the molecular mechanisms by which it exerts its functions, as well as the underlying mechanism of its dysregulation. We also discussed the therapeutic implications of targeting ALKBH5 in cancer and potential ALKBH5-targeting strategies.
    Keywords:  ALKBH5; Cancer; Gene regulation; RNA demethylation; Therapeutic target; m6A modification
    DOI:  https://doi.org/10.1186/s13045-022-01224-4
  2. Cell Death Dis. 2022 Jan 21. 13(1): 72
    N6-methyladenosine demethylase FTO promotes growth and metastasis of gastric cancer via m6A modification of caveolin-1 and metabolic regulation of mitochondrial dynamics.
    You Zhou, Qi Wang, Haifeng Deng, Bin Xu, Yi Zhou, Jian Liu, Yingting Liu, Yufang Shi, Xiao Zheng, Jingting Jiang.
      Gastric cancer (GC) is the fifth most common tumor and the third most deadly cancer worldwide. N6-methyladenosine (m6A) modification has been reported to play a regulatory role in human cancers. However, the exact role of m6A in GC remains largely unknown, and the dysregulation of m6A on mitochondrial metabolism has never been studied. In the present study, we demonstrated that FTO, a key demethylase for RNA m6A modification, was up-regulated in GC tissues, especially in tissues with liver metastasis. Functionally, FTO acted as a promoter for the proliferation and metastasis in GC. Moreover, FTO enhanced the degradation of caveolin-1 mRNA via its demethylation, which regulated the mitochondrial fission/fusion and metabolism. Collectively, our current findings provided some valuable insights into FTO-mediated m6A demethylation modification and could be used as a new strategy for more careful surveillance and aggressive therapeutic intervention.
    DOI:  https://doi.org/10.1038/s41419-022-04503-7
  3. J Biol Chem. 2022 Jan 13. pii: S0021-9258(22)00030-8. [Epub ahead of print] 101590
    The METTL5-TRMT112 N6-methyladenosine methyltransferase complex regulates mRNA translation via 18S rRNA methylation.
    Caraline Sepich-Poore, Zhong Zheng, Emily Schmitt, Kailong Wen, Zijie Scott Zhang, Xiao-Long Cui, Qing Dai, Allen C Zhu, Linda Zhang, Arantxa Sanchez Castillo, Haiyan Tan, Junmin Peng, Xiaoxi Zhuang, Chuan He, Sigrid Nachtergaele.
      Ribosomal RNAs (rRNAs) have long been known to carry chemical modifications, including 2'O-methylation, pseudouridylation, N6-methyladenosine (m6A), and N6,6-dimethyladenosine. While the functions of many of these modifications are unclear, some are highly conserved and occur in regions of the ribosome critical for mRNA decoding. Both 28S rRNA and 18S rRNA carry single m6A sites, and while the methyltransferase ZCCHC4 has been identified as the enzyme responsible for the 28S rRNA m6A modification, the methyltransferase responsible for the 18S rRNA m6A modification has remained unclear. Here, we show that the METTL5-TRMT112 methyltransferase complex installs the m6A modification at position 1832 of human 18S rRNA. Our work supports findings that TRMT112 is required for METTL5 stability and reveals that human METTL5 mutations associated with microcephaly and intellectual disability disrupt this interaction. We show that loss of METTL5 in human cancer cell lines and in mice regulates gene expression at the translational level; additionally, Mettl5 knockout mice display reduced body size and evidence of metabolic defects. While recent work has focused heavily on m6A modifications in mRNA and their roles in mRNA processing and translation, we demonstrate here that deorphanizing putative methyltransferase enzymes can reveal previously unappreciated regulatory roles for m6A in noncoding RNAs.
    Keywords:  RNA methylation; m(6)A methylation; methyltransferase; post-transcriptional regulation; ribosomal RNA; translation regulation
    DOI:  https://doi.org/10.1016/j.jbc.2022.101590
  4. Cell Biol Toxicol. 2022 Jan 17.
    METTL3 facilitates multiple myeloma tumorigenesis by enhancing YY1 stability and pri-microRNA-27 maturation in m6A-dependent manner.
    Feifei Che, Xuemei Ye, Yu Wang, Xuemei Wang, Shuyue Ma, Yawen Tan, Yan Mao, Ziyue Luo.
      Multiple myeloma (MM) is a pernicious plasma cell disorder and has a poor prognosis. N6-methyladenosine (m6A) is an abundant epigenetic RNA modification and is important in cancer progression. Nevertheless, the function of m6A and its regulator METTL3 in MM are rarely reported. Here, we identified the m6A "writers", METTL3, was enhanced in MM and found that Yin Yang 1 (YY1) and primary-miR-27a-3p were the potential target for METTL3. METTL3 promoted primary-miR-27a-3p maturation and YY1 mRNA stability in an m6A manner. YY1 also was found to facilitate miR-27a-3p transcription. METTL3 affected the growth, apoptosis, and stemness of MM cells through accelerating the stability of YY1 mRNA and the maturation of primary-miR-27a-3p in vitro and in vivo. Our results reveal the key function of the METTL3/YY1/miR-27a-3p axis in MM and may provide fresh insights into MM therapy.
    Keywords:  METTL3; Multiple myeloma; N 6-methyladenosine; YY1; miR-27a-3p
    DOI:  https://doi.org/10.1007/s10565-021-09690-1
  5. Mol Ther Nucleic Acids. 2022 Mar 08. 27 547-561
    METTL14-mediated Lnc-LSG1 m6A modification inhibits clear cell renal cell carcinoma metastasis via regulating ESRP2 ubiquitination.
    Danyang Shen, Lifeng Ding, Zeyi Lu, Ruyue Wang, Chenhao Yu, Huan Wang, Qiming Zheng, Xuliang Wang, Wanjiang Xu, Haifeng Yu, Liwei Xu, Mingchao Wang, Shicheng Yu, Shibin Zhu, Jun Qian, Liqun Xia, Gonghui Li.
      Clear cell renal cell carcinoma (ccRCC) is the most lethal urological cancer and is characterized by a high rate of metastasis and relapse. N6-Methyladenosine (m6A) is implicated in various stages of cancer development. However, a thorough understanding of m6A-modified lncRNAs in ccRCC is lacking. The results showed that METTL14 had decreased expression in ccRCC tissues. In addition, the expression of METTL14 was negatively correlated to the prognosis, stage, and ccRCC tumor grade. The silencing of METTL14 was shown to significantly increase metastasis in vitro and in vivo. High-throughput methylated RNA immunoprecipitation sequencing (MeRIP-seq) showed that the m6A levels of Lnc-LSG1 could be regulated by METTL14. Lnc-LSG1 can directly bind to ESRP2 protein and promote ESRP2 degradation via facilitating ESRP2 ubiquitination. However, m6A modification on Lnc-LSG1 can block the interaction between Lnc-LSG1 and ESRP2 via the m6A reader, YTHDC1. Taken together, our findings unraveled the novel mechanism of METTL14 inhibiting ccRCC progression, and explored the correlation between m6A and lncRNA in ccRCC for the first time.
    Keywords:  ESRP2; Lnc-LSG1; METTL14; N6-methyladenosine; YTHDC1; clear cell renal cell carcinoma
    DOI:  https://doi.org/10.1016/j.omtn.2021.12.024
  6. Eur J Med Chem. 2022 Jan 12. pii: S0223-5234(22)00020-4. [Epub ahead of print]230 114118
    Roles and drug development of METTL3 (methyltransferase-like 3) in anti-tumor therapy.
    Pengfei Xu, Raoling Ge.
      Methyltransferase complex, such as METTL3/METTL14/WTP, catalyze N6-methyladenosine (m6A), which is the most abundant mRNA modification in mammals. Besides acting as a m6A methyltransferase, METTL3 also regulates mRNA translation and other biological processes. Studies have identified numerous roles and molecular mechanisms associated with METTL3 in multiple biological processes especially in tumors in recent years. Furthermore, targeting METTL3 as an efficient therapeutic way for the treatment of different kinds of tumors has gained a lot of attention. However, these findings and researches have not been summarized. In this review, the most recent important roles of METTL3 in various tumors including acute myeloid leukemia, lung cancer, breast cancer, liver cancer, gastric cancer, pancreatic cancer, colorectal cancer, bladder cancer, prostate cancer and glioblastoma were systematically summarized. In addition, disclosed METTL3 inhibitors recently were also summarized and discussed for medicinal chemists investigating METTL3 inhibitors with different skeleton structures for the application of human cancer therapy.
    Keywords:  Cancer therapy; Drug discovery; METTL3; Medicinal chemistry; m(6)A modification
    DOI:  https://doi.org/10.1016/j.ejmech.2022.114118
  7. Bioengineered. 2022 Feb;13(2): 3108-3121
    Long intergenic non-protein coding RNA 1273 confers sorafenib resistance in hepatocellular carcinoma via regulation of methyltransferase 3.
    Huifang Kong, Jie Sun, Wei Zhang, Huixin Zhang, Hong Li.
      Hepatocellular carcinoma (HCC) is often diagnosed in patients with advanced disease who are ineligible for curative surgical therapies. Sorafenib is a first-line agent approved for the treatment of advanced HCC. However, the frequent resistance of HCC cells to sorafenib greatly reduces its efficacy. Herein, we describe a novel long non-coding RNA (lncRNA) conferring sorafenib resistance. Long intergenic non-protein coding RNA 1273 (LINC01273) was significantly overexpressed in human HCC and sorafenib-resistant tissues, linking it to poor overall and relapse-free survival. We established sorafenib-resistant Huh7 (Huh7-SR) and SMMC-7721 (SMMC-7721-SR) cells, and found that the knockdown of LINC01273 repressed the viability, colony formation, and DNA synthesis rate of Huh7-SR and SMMC-7721-SR cells. The level of N6-methyladenosine (m6A) in sorafenib-resistant HCC cells was significantly decreased, which was rescued by LINC01273 silencing. Mechanistically, LINC01273 complementarity bound to miR-600, served as a 'reservoir' increasing miR-600 stability, and facilitating miR-600 targeting methyltransferase 3 (METTL3), a m6A 'writer', resulting in reducing METTL3 level. In addition, LINC01273 was modified with m6A, METTL3 increased LINC01273 m6A modification, followed by LINC01273 decay in the presence of YTHDF2, a m6A 'reader'. Our findings reveal the key role of LINC01273 in sorafenib-resistant HCC cells, and targeting of the newly identified LINC01273/miR-600/METTL3 feedback regulatory axis may be a promising effective intervention for HCC patients with sorafenib resistance.
    Keywords:  Hepatocellular carcinoma; LINC01273; N6-methyladenosine; sorafenib resistance
    DOI:  https://doi.org/10.1080/21655979.2022.2025701
  8. BMC Genom Data. 2022 Jan 18. 23(1): 8
    N6-Methyladenosine-Related lncRNAs as potential biomarkers for predicting prognoses and immune responses in patients with cervical cancer.
    He Zhang, Weimin Kong, Xiaoling Zhao, Chao Han, Tingting Liu, Jing Li, Dan Song.
      BACKGROUND: Several recent studies have confirmed epigenetic regulation of the immune response. However, the potential role of RNA N6-methyladenosine (m6A) modifications in cervical cancer and tumour microenvironment (TME) cell infiltration remain unclear.RESULTS: We evaluated and analysed m6A modification patterns in 307 cervical cancer samples from The Cancer Genome Atlas (TCGA) dataset based on 13 m6A regulators. Pearson correlation analysis was used to identify lncRNAs associated with m6A, followed by univariate Cox regression analysis to screen their prognostic role in cervical cancer patients. We also correlated TME cell infiltration characteristics with modification patterns. We screened six m6A-associated lncRNAs as prognostic lncRNAs and established the prognostic profile of m6A-associated lncRNAs by least absolute shrinkage and choice of operator (LASSO) Cox regression. The corresponding risk scores of the patients were derived based on their prognostic features, and the correlation between this feature model and disease prognosis was analysed. The prognostic model constructed based on the TCGA-CESC (The Cancer Genome Cervical squamous cell carcinoma and endocervical adenocarcinoma) dataset showed strong prognostic power in the stratified analysis and was confirmed as an independent prognostic indicator for predicting the overall survival of patients with CESC. Enrichment analysis showed that biological processes, pathways, and markers associated with malignancy were more common in the high-risk subgroup. Risk scores were strongly correlated with the tumour grade. ECM receptor interactions and pathways in cancer were enriched in Cluster 2, while oxidative phosphorylation and other biological processes were enriched in Cluster 1. The expression of immune checkpoint molecules, including programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1), was significantly increased in the high-risk subgroup, suggesting that this prognostic model could be a predictor of immunotherapy.
    CONCLUSIONS: This study reveals that m6A modifications play an integral role in the diversity and complexity of TME formation. Assessing the m6A modification patterns of individual tumours will help improve our understanding of TME infiltration characteristics and thus guide immunotherapy more effectively. We also developed an independent prognostic model based on m6A-associated lncRNAs as a predictor of overall survival, which can also be used as a predictor of immunotherapy.
    Keywords:  Cervical cancer; Immunotherapy; Stroma; Tumour microenvironment; m6A
    DOI:  https://doi.org/10.1186/s12863-022-01024-2
  9. Mol Ther. 2022 Jan 13. pii: S1525-0016(22)00019-3. [Epub ahead of print]
    RNA m6A methylation regulates the dissemination of cancer cells via modulating expression and membrane localization of β-catenin.
    Jiexin Li, Guoyou Xie, Yifan Tian, Wanglin Li, Yingmin Wu, Feng Chen, Yu Lin, Xinyao Lin, Shannon Wing-Ngor Au, Jie Cao, Weiling He, Hongsheng Wang.
      N6-methyladenosine (m6A) methylation, which is modified by METTL3/METTL14 complex, is a dominant internal modification in mammalian RNA and tightly links to cancer progression. Here, we reveal that METTL3-promoted cell migration, invasion and epithelial to mesenchymal transition (EMT) are associated with the expression and membrane localization of β-catenin (encoded by CTNNB1), as opposed to Wnt signaling activation in various types of cancer cells, including cervical, lung, and liver cancers. Specifically, METTL3 regulates the transcription, mRNA decay, translation and sub-cellular localization of β-catenin. For CTNNB1 expression, METTL3 indirectly suppresses CTNNB1 transcription via stabilizing its transcription suppressor E2F1 mRNA; deposition of 5'UTR m6A in CTNNB1 promotes its decay in a content-dependent manner via YTHDF2 recognition; 5'UTR m6A in CTNNB1 suppresses its translation efficiency, while global METTL3 level controls the canonical and non-canonical translation of CTNNB1, which is probably associated with the interaction between YTHDF1 and eIF4E1/eIF4E3. For β-catenin translocation, METTL3 represses membrane localization of β-catenin and its interaction with E-Cadherin by downregulating c-Met kinase, leading to the inhibition of cell motility. In vitro, in vivo and clinical analysis confirm the essential roles of β-catenin and its expression regulators in cancer cell dissemination. The findings not only expand our understanding of m6A modification and its roles in gene expression and subcellular localization of targets, but also suggest that METTL3/β-catenin axis might be a potential target to inhibit cancer metastasis.
    DOI:  https://doi.org/10.1016/j.ymthe.2022.01.019
  10. Nutrients. 2022 Jan 07. pii: 251. [Epub ahead of print]14(2):
    Intermittent Fasting Improves High-Fat Diet-Induced Obesity Cardiomyopathy via Alleviating Lipid Deposition and Apoptosis and Decreasing m6A Methylation in the Heart.
    Zujie Xu, Ying Qin, Binbin Lv, Zhenjun Tian, Bing Zhang.
      Intermittent fasting (IF) plays an essential role in improving lipid metabolism disorders caused by metabolic cardiomyopathy. Growing evidence revealed that N6-methyladenosine (m6A) RNA methylation is related to obesity and lipid metabolic. Our study aimed to assess the beneficial effects of IF on lipid deposition, apoptosis, and m6A methylation in high-fat diet (HFD)-induced obesity cardiomyopathy. Male C57BL/6J mice were fed a normal diet (ND) or HFD ad libitum for 13 weeks, after which time a subgroup of HFD mice were subjected to IF for 24 h and fed HFD in the other day for 8 weeks. We found that IF intervention significantly improved cardiac functional and structural impairment and serum lipid metabolic disorder induced by HFD. Furthermore, IF intervention decreased the mRNA levels of the fatty acid uptake genes of FABP1, FATP1, and CD36 and the fatty acid synthesis genes of SREBF1, FAS, and ACCα and increased the mRNA levels of the fatty acid catabolism genes of ATGL, HSL, LAL, and LPL in cardiac tissueof HFD-induced obese mice. TUNEL-positive cells, Bax/Bcl-2 ratio, and Cleaved Caspase-3 protein expression in HFD-induced obese mice hearts was down-regulated by IF intervention. In addition, IF intervention decreased the m6A methylation levels and METTL3 expression and increased FTO expression in HFD-induced obesity cardiomyopathy. In conclusion, our findings demonstrate that IF attenuated cardiac lipid deposition and apoptosis, as well as improved cardiac functional and structural impairment in HFD-induced obesity cardiomyopathy, by a mechanism associated with decreased m6A RNA methylation levels.
    Keywords:  N6-methyladenosine methylation; apoptosis; high-fat diet; intermittent fasting; lipid deposition; obesity cardiomyopathy
    DOI:  https://doi.org/10.3390/nu14020251
  11. Cancer Lett. 2022 Jan 13. pii: S0304-3835(22)00021-0. [Epub ahead of print]
    ZC3H13-mediated N6-methyladenosine modification of PHF10 is impaired by fisetin which inhibits the DNA damage response in pancreatic cancer.
    Chaojie Huang, Senhao Zhou, Chaolei Zhang, Yifeng Jin, Gao Xu, Liangjing Zhou, Guoping Ding, Tianshu Pang, Shengnan Jia, Liping Cao.
      DNA damage repair is a major barrier for chemotherapy efficacy of pancreatic ductal adenocarcinoma (PDAC), including the efficacy of platinum-based and gemcitabine/nab-paclitaxel treatments. N6-methyladenosine modifications (m6A) have recently been reported to play a role in homologous recombination (HR) repair of DNA double strand breaks (DSBs); however, the mechanism of action remains unknown. Our previous work indicated that fisetin may be a promising anti-tumour agent that induces DNA damage. In this study, we reported that fisetin induced DSBs and suppressed HR repair through m6A modification in PDAC cells. The m6A writer ZC3H13 and PHF10, which is a subunit of the PBAF chromatin remodelling complex, were identified as the main molecules affected by fisetin treatment. To our knowledge, it's the first time that PHF10 was found and involved in the DNA damage response. PHF10 loss-of-function resulted in elevated recruitment of γH2AX, RAD51, and 53BP1 to DSB sites and decreased HR repair efficiency. Moreover, ZC3H13 knockdown downregulated the m6A methylation of PHF10 and decreased PHF10 translation in a YTHDF1-dependent manner. In conclusion, our study demonstrates that fisetin enhanced DSBs via ZC3Hl3-mediated m6A modification of PHF10, which may provide insight into novel therapeutic approaches for PDAC.
    Keywords:  DNA damage response; Fisetin; N6-methyladenosine modification; PHF10; ZC3H13
    DOI:  https://doi.org/10.1016/j.canlet.2022.01.013
  12. Am J Transl Res. 2021 ;13(12): 13423-13437
    METTL3 facilitates the progression of hepatocellular carcinoma by modulating the m6A level of USP7.
    Yaqin Li, Xianyi Cheng, Yihua Chen, Tao Zhou, Dezhi Li, Wei V Zheng.
      OBJECTIVE: To explore whether METTL3 was involved in the pathogenesis of hepatocellular carcinoma (HCC) by modulating the m6A level of USP7.METHODS: We performed qRT-PCR and western blot assays to detect the expression level of METTL3 in HCC tissues and paired adjacent normal tissues, as well as HCC cell lines. The level of m6A in HCC tissues and cells was quantitatively analyzed by m6A RNA Methylation Quantitative Kit. We examined the effect of METTL3 on cell proliferation ability by CCK-8 and EdU assays, and examined cell migration and cell invasion ability by Transwell assay. It was predicted via bioinformatics tool that USP7 may undergo methylation in HCC. Subsequently, we performed qRT-PCR assay to detect the expression level of USP7 in HCC tissues and analyzed its correlation with the expression level of METTL3. We verified the regulatory relationship between METTL3/USP7 and transfected USP7 siRNA in cells to detect its effects on cell invasion, migration and proliferation. The regulatory effect of METTL3 on USP7 in HCC was analyzed by corresponding experiments.
    RESULTS: The qRT-PCR results indicated that METTL3 was highly expressed in HCC tissues and cell lines. The level of m6A was remarkably increased in HCC tissues and cell lines. Besides, the elevated METTL3 expression was related to worse overall survival. The abilities of cell invasion, migration and proliferation were remarkably attenuated by down-regulation of METTL3 expression. Through bioinformatics analysis, it was found that USP7 might be regulated by METTL3 to undergo methylation modification. The qRT-PCR results showed that the USP7 was highly expressed in HCC tissues, and was positively correlated with the level of METTL3. Further experiments showed that down-regulation of USP7 could reduce cell proliferation, migration, and invasion. METTL3 could positively regulate the malignant phenotype of USP7 in HCC.
    CONCLUSION: METTL3 might regulate the expression of USP7 through m6A methylation and facilitate the invasion, migration and proliferation of HCC cells.
    Keywords:  METTL3; RNA methylation; cell invasion; cell migration; cell proliferation
  13. Inflamm Res. 2022 Jan 21.
    Dihydroartemisinin alleviates AngII-induced vascular smooth muscle cell proliferation and inflammatory response by blocking the FTO/NR4A3 axis.
    Yan-Bing Huo, Xiang Gao, Qi Peng, Qiang Nie, Wei Bi.
      OBJECTIVE: Inflammation and proliferation of vascular smooth muscle cells (VSMCs), induced by angiotensin II (AngII) and other growth factors, play important roles in the pathogenesis of hypertension, restenosis, and atherosclerosis. Dihydroartemisinin (DHA) exhibits broad protective effects. However, the effects of DHA on AngII-induced inflammation and proliferation of VSMCs remain unknown.MATERIALS AND METHODS: AngII was used to construct VSMCs and vascular inflammation model in vitro and in vivo. The protective roles of DHA in inflammatory response and proliferation were evaluated through CCK-8, BrdU assay and immunofluorescence staining. The level of mRNA N6-methyladenosine was measured by m6A-RNA immunoprecipitation (MeRIP) assay. Western blot and quantitative real-time PCR were used to investigate the relationship between FTO and its potential downstream signaling molecules.
    RESULTS: In the present study, we found that DHA significantly suppressed AngII-induced proliferation of VSMCs and the expression of IL-6 and Ccl2 in a dose-dependent manner. Additionally, we confirmed that fat mass and obesity-associated (FTO) plays a critical role in AngII-induced VSMC proliferation and inflammation. FTO knockdown increased the methylation level of NR4A3 mRNA, whereas FTO, but not mutated FTO overexpression, reduced the methylation level of NR4A3 mRNA. These results suggest that DHA plays a protective role in AngII-induced VSMC proliferation and the associated inflammation by inhibiting the FTO/NR4A3 axis.
    CONCLUSION: Our findings provide new insight into the mechanisms of DHA and its critical role in the pathogenesis of hypertension-related vascular complications.
    Keywords:  AngII; Dihydroartemisinin; FTO; NR4A3; VSMC
    DOI:  https://doi.org/10.1007/s00011-021-01533-3
  14. Mol Oncol. 2022 Jan 19.
    Downregulation of m6 A writer complex member METTL14 in bladder urothelial carcinoma suppresses tumor aggressiveness.
    Catarina Guimarães-Teixeira, João Lobo, Vera Miranda-Gonçalves, Daniela Barros-Silva, Cláudia Martins-Lima, Sara Monteiro-Reis, José Pedro Sequeira, Isa Carneiro, Margareta P Correia, Rui Henrique, Carmen Jerónimo.
      N6-methyladenosine (m6 A) and its regulatory proteins have been associated with tumorigenesis in several cancer types. However, knowledge on the mechanistic network related to m6 A in bladder cancer (BlCa) is rather limited, requiring further investigation of its functional role. We aimed to uncover the biological role of m6 A and related proteins in BlCa and understand how this influences tumor aggressiveness. N6-adenosine-methyltransferase catalytic subunit (METTL3), N6-adenosine-methyltransferase non-catalytic subunit (METTL14), protein virilizer homolog (VIRMA) and RNA demethylase ALKBH5 (ALKBH5) had significantly lower expression levels in BlCa compared to in normal urothelium. METTL14 knockdown led to disruption of the remaining methyltransferase complex and a decrease in m6 A abundance, as well as overall reduced tumor aggressiveness (decreased cell invasion and migration capacity, and increased apoptosis). Furthermore, in vivo, METTL14 knockdown caused tumor size reduction. Collectively, we propose methyltransferase METTL14 as a key component for m6 A RNA deposit and that it is closely related to BlCa progression, playing an important role in tumor aggressiveness. These data contribute to a better understanding of the m6 A writer complex, which might constitute an appealing therapeutic target.
    Keywords:  Bladder cancer; Epitranscriptome; METTL14; N6-methyladenosine; RNA modifications; m6A-regulators proteins
    DOI:  https://doi.org/10.1002/1878-0261.13181
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