bims-rimeca Biomed News
on RNA methylation in cancer
Issue of 2022‒05‒22
eight papers selected by
Sk Ramiz Islam
Saha Institute of Nuclear Physics
  1. METTL3 promotes colorectal cancer metastasis by stabilizing PLAU mRNA in an m6A-dependent manner.
  2. METTL3-Mediated ADAMTS9 Suppression Facilitates Angiogenesis and Carcinogenesis in Gastric Cancer.
  3. Methyltransferase-like 3 Aggravates HCC Development via Mediating N6-Methyladenosine of Ubiquitin-Specific Protease 7.
  4. m6A demethylase FTO promotes tumor progression via regulation of lipid metabolism in esophageal cancer.
  5. METTL16 promotes hepatocellular carcinoma progression through downregulating RAB11B-AS1 in an m6A-dependent manner.
  6. m6A Reader Igf2bp1 Regulates the Inflammatory Responses of Microglia by Stabilizing Gbp11 and Cp mRNAs.
  7. Identification and validation of the N6-methyladenosine RNA methylation regulator ZC3H13 as a novel prognostic marker and potential target for hepatocellular carcinoma.
  8. Identification and Verification of m7G Modification Patterns and Characterization of Tumor Microenvironment Infiltration via Multi-Omics Analysis in Clear Cell Renal Cell Carcinoma.
  1. Biochem Biophys Res Commun. 2022 May 06. pii: S0006-291X(22)00689-1. [Epub ahead of print]614 9-16
    METTL3 promotes colorectal cancer metastasis by stabilizing PLAU mRNA in an m6A-dependent manner.
    Ting Yu, Jingya Liu, Yiwen Wang, Wenlong Chen, Zhixian Liu, Lingjun Zhu, Wei Zhu.
      Colorectal cancer (CRC) is one of the most common tumors and ranks second in tumor mortality. N6-methyladenosine (m6A) modification is the most prevalent RNA modification in eukaryotes. As the critical m6A methyltransferase, the role of METTL3 in the metastasis regulation of CRC might be controversial and need to be further explored. In this study, we confirmed that METTL3 could promoted CRC metastasis in vitro and in vivo. METTL3 was upregulated in CRC tissues and led to poor survival in CRC metastasis. We found METTL3 upregulated PLAU mRNA in an m6A-dependent manner, and then participated in MAPK/ERK pathway to promote angiogenesis and metastasis in CRC. Our study provided new therapeutic targets in CRC metastasis treatment.
    Keywords:  Colorectal cancer; METTL3; Metastasis; PLAU; m6A
    DOI:  https://doi.org/10.1016/j.bbrc.2022.04.141
  2. Front Oncol. 2022 ;12 861807
    METTL3-Mediated ADAMTS9 Suppression Facilitates Angiogenesis and Carcinogenesis in Gastric Cancer.
    Nuofan Wang, Xinying Huo, Baoguo Zhang, Xiaoxiang Chen, Shuli Zhao, Xuesong Shi, Hao Xu, Xiaowei Wei.
      The role of methyltransferase-like 3 (METTL3), which participates in catalyzing N-methyladenosine (m6A) RNA modification, in gastric cancer (GC) is unclear. Here, we found that METTL3 was overexpressed in human GC. Functionally, we verified that METTL3 promoted tumor cell proliferation and angiogenesis through a series of phenotypic experiments. Subsequently, ADAMTS9 was identified as the downstream effector of METTL3 in GC, which could be degraded by the YTHDF2-dependent pathway. Finally, the data suggested that METTL3 might facilitate GC progression through the ADAMTS9-mediated PI3K/AKT pathway. Our study unveiled the fundamental mechanisms of METTL3 in GC progression. The clinical value of METTL3 in GC deserves further exploration.
    Keywords:  ADAMTS9; METTL3; N6-methyladenosine; YTHDF2; gastric cancer
    DOI:  https://doi.org/10.3389/fonc.2022.861807
  3. J Oncol. 2022 ;2022 6167832
    Methyltransferase-like 3 Aggravates HCC Development via Mediating N6-Methyladenosine of Ubiquitin-Specific Protease 7.
    Daiyue Yuan, Jie Chen, Qingya Hao, Peng Zhang, Zhong Chen.
      We aimed to investigate the role of methyltransferase-like 3 (METTL3) in regulating HCC by mediating m6A level of ubiquitin-specific protease (USP7). METTL3 levels and m6A contents in HCC tissues and cells were detected. Potential correlations between METTL3 level and lymphatic metastasis, tumor size, tumor staging, and overall survival of HCC patients were analyzed. Moreover, its regulatory effects on proliferative, migratory, and invasive rates of HCC cells were examined. Potential methylation of USP7 in HCC was predicted using an online software, and the correlation between USP7 and METTL3 was assessed. METTL3 and m6A were increased both in HCC cells and tissues. High level of METTL3 was associated with the incidence of lymphatic metastasis, large tumor size, advanced tumor staging, and low overall survival of HCC. Silencing of METTL3 reduced proliferation, migration, and invasion rates. USP7 was predicted to have a methylation site regulated by METTL3. It was upregulated in HCC and associated with METTL3 level positively. USP7 silencing decreased proliferation, migration, and invasion rates of HCC cells. METTL3 promotes HCC to proliferate, migrate, and invade by regulating m6A methylation of USP7.
    DOI:  https://doi.org/10.1155/2022/6167832
  4. Cell Biosci. 2022 May 14. 12(1): 60
    m6A demethylase FTO promotes tumor progression via regulation of lipid metabolism in esophageal cancer.
    Xiaoran Duan, Li Yang, Liuya Wang, Qinghua Liu, Kai Zhang, Shasha Liu, Chaojun Liu, Qun Gao, Lifeng Li, Guohui Qin, Yi Zhang.
      BACKGROUND: Epitranscriptomics studies have contributed greatly to the development of research on human cancers. In recent years, N6-methyladenosine (m6A), an RNA modification on the N-6 position of adenosine, has been found to play a potential role in epigenetic regulation. Therefore, we aimed to evaluate the regulation of cancer progression properties by m6A.RESULTS: We found that m6A demethylase fat mass and obesity-associated protein (FTO) was highly expressed in esophageal cancer (EC) stem-like cells, and that its level was also substantially increased in EC tissues, which was closely correlated with a poor prognosis in EC patients. FTO knockdown significantly inhibited the proliferation, invasion, stemness, and tumorigenicity of EC cells, whereas FTO overexpression promoted these characteristics. Furthermore, integrated transcriptome and meRIP-seq analyses revealed that HSD17B11 may be a target gene regulated by FTO. Moreover, FTO promoted the formation of lipid droplets in EC cells by enhancing HSD17B11 expression. Furthermore, depleting YTHDF1 increased the protein level of HSD17B11.
    CONCLUSIONS: These data indicate that FTO may rely on the reading protein YTHDF1 to affect the translation pathway of the HSD17B11 gene to regulate the formation of lipid droplets in EC cells, thereby promoting the development of EC. The understanding of the role of epitranscriptomics in the development of EC will lay a theoretical foundation for seeking new anticancer therapies.
    Keywords:  Demethylase FTO; Esophageal cancer; Lipid Metabolism; m6A
    DOI:  https://doi.org/10.1186/s13578-022-00798-3
  5. Cell Mol Biol Lett. 2022 May 20. 27(1): 41
    METTL16 promotes hepatocellular carcinoma progression through downregulating RAB11B-AS1 in an m6A-dependent manner.
    Yun-Zhang Dai, Yong-da Liu, Jie Li, Mei-Ting Chen, Mei Huang, Fang Wang, Qing-Song Yang, Ji-Hang Yuan, Shu-Han Sun.
      BACKGROUND: The molecular mechanisms driving hepatocellular carcinoma (HCC) remain largely unclear. As one of the major epitranscriptomic modifications, N6-methyladenosine (m6A) plays key roles in HCC. The aim of this study was to investigate the expression, roles, and mechanisms of action of the RNA methyltransferase methyltransferase-like protein 16 (METTL16) in HCC.METHODS: The expression of METTL16 and RAB11B-AS1 was determined by RT-qPCR. The regulation of RAB11B-AS1 by METTL16 was investigated by RNA immunoprecipitation (RIP), methylated RIP (MeRIP), and RNA stability assays. In vitro and in vivo gain- and loss-of-function assays were performed to investigate the roles of METTL16 and RAB11B-AS1.
    RESULTS: METTL16 was upregulated in HCC, and its increased expression was correlated with poor prognosis of HCC patients. METTL16 promoted HCC cellular proliferation, migration, and invasion, repressed HCC cellular apoptosis, and promoted HCC tumoral growth in vivo. METTL16 directly bound long noncoding RNA (lncRNA) RAB11B-AS1, induced m6A modification of RAB11B-AS1, and decreased the stability of RAB11B-AS1 transcript, leading to the downregulation of RAB11B-AS1. Conversely to METTL16, RAB11B-AS1 is downregulated in HCC, and its decreased expression was correlated with poor prognosis of patients with HCC. Furthermore, the expression of RAB11B-AS1 was negatively correlated with METTL16 in HCC tissues. RAB11B-AS1 repressed HCC cellular proliferation, migration, and invasion, promoted HCC cellular apoptosis, and inhibited HCC tumoral growth in vivo. Functional rescue assays revealed that overexpression of RAB11B-AS1 reversed the oncogenic roles of METTL16 in HCC.
    CONCLUSIONS: This study identified the METTL16/RAB11B-AS1 regulatory axis in HCC, which represented novel targets for HCC prognosis and treatment.
    Keywords:  Hepatocellular carcinoma; Long noncoding RNA; N 6-methyladenosine; RNA methyltransferase; Tumor progression
    DOI:  https://doi.org/10.1186/s11658-022-00342-8
  6. Front Immunol. 2022 ;13 872252
    m6A Reader Igf2bp1 Regulates the Inflammatory Responses of Microglia by Stabilizing Gbp11 and Cp mRNAs.
    Lu Ding, Huiran Wu, Yi Wang, Yun Li, Zhanping Liang, Xiaohuan Xia, Jialin C Zheng.
      Microglia are brain resident cells that function as brain phagocytic macrophages. The inflammatory responses of microglia induced by pathologic insults are key regulators in the progression of various neurological disorders. Currently, little is known about how these responses are regulated intrinsically. Here, it is observed that LPS-activated microglia exhibit distinct N6-methyladenosine (m6A) methylation patterns that are positively correlated with the expression patterns of corresponding mRNAs. High-throughput analyses and molecular studies both identified Igf2bp1 as the most significantly regulated m6A modifiers in activated microglia. Perturbation of function approaches further indicated Igf2bp1 as a key mediator for LPS-induced m6A modification and microglial activation presumably via enhancing the m6A methylation and stability of Gbp11 and Cp mRNAs. Thus, our study provides a possible mechanism for the m6A methylation-mediated microglia regulation and identifies Igf2bp1 as a potential target for modulating the inflammatory responses of microglia.
    Keywords:  Cp; Gbp11; Igf2bp1; m6A reader; microglial activation; neuroinflammation
    DOI:  https://doi.org/10.3389/fimmu.2022.872252
  7. Int J Med Sci. 2022 ;19(4): 618-630
    Identification and validation of the N6-methyladenosine RNA methylation regulator ZC3H13 as a novel prognostic marker and potential target for hepatocellular carcinoma.
    Shuang Wu, Guifang He, Shihai Liu, Yongxian Cao, Chao Geng, Huazheng Pan.
      N6-methyladenosine (m6A) RNA methylation has been implicated in various malignancies. This study aimed to identify prognostic signature based on m6A methylation regulators for hepatocellular carcinoma (HCC) and provide candidate targets for HCC treatment. In this study, the expression levels, prognostic values, correlation with tumor grades and genetic variations of m6A-related genes in HCC were evaluated using bioinformatics analyses. Interestingly, the results show that methyltransferase zinc finger CCCH-type containing 13 (ZC3H13) was expressed at a significantly low level in HCC. Survival outcome analysis suggested that significant correlations existed between ZC3H13 downregulation and poor overall survival (OS) and poor recurrence-free survival (RFS) in HCC patients. Therefore, ZC3H13 was chosen for further experimental validation. The expression of ZC3H13 in HCC cell lines was investigated by western blotting. Knockdown of ZC3H13 significantly enhanced the migration and invasion of HCC cells, as demonstrated by wound healing and transwell assays. Moreover, upregulating ZC3H13 repressed the growth of xenograft tumors in vivo. Functional and pathway enrichment analyses indicated that ZC3H13 might be involved in transcriptional dysregulation or the JAK-STAT signaling pathway in cancer. Additionally, ZC3H13 expression was significantly correlated with lymphocytes and immunomodulators. Therefore, ZC3H13 is a promising candidate as a novel biomarker and therapeutic target for HCC.
    Keywords:  Bioinformatics analyses; Hepatocellular Carcinoma; M6A-related genes; Prognostic value; ZC3H13
    DOI:  https://doi.org/10.7150/ijms.69645
  8. Front Immunol. 2022 ;13 874792
    Identification and Verification of m7G Modification Patterns and Characterization of Tumor Microenvironment Infiltration via Multi-Omics Analysis in Clear Cell Renal Cell Carcinoma.
    Kai Dong, Di Gu, Jiazi Shi, Yewei Bao, Zhibin Fu, Yu Fang, Le Qu, Wentong Zhu, Aimin Jiang, Linhui Wang.
      The epigenetic modification of tumorigenesis and progression in neoplasm has been demonstrated in recent studies. Nevertheless, the underlying association of N7-methylguanosine (m7G) regulation with molecular heterogeneity and tumor microenvironment (TME) in clear cell renal cell carcinoma (ccRCC) remains unknown. We explored the expression profiles and genetic variation features of m7G regulators and identified their correlations with patient outcomes in pan-cancer. Three distinct m7G modification patterns, including MGCS1, MGCS2, and MGCS3, were further determined and systematically characterized via multi-omics data in ccRCC. Compared with the other two subtypes, patients in MGCS3 exhibited a lower clinical stage/grade and better prognosis. MGCS1 showed the lowest enrichment of metabolic activities. MGCS2 was characterized by the suppression of immunity. We then established and validated a scoring tool named m7Sig, which could predict the prognosis of ccRCC patients. This study revealed that m7G modification played a vital role in the formation of the tumor microenvironment in ccRCC. Evaluating the m7G modification landscape helps us to raise awareness and strengthen the understanding of ccRCC's characterization and, furthermore, to guide future clinical decision making.
    Keywords:  N7-methylguanosine; drug response; immune microenvironment; prognosis; renal cell carcinoma; single cell
    DOI:  https://doi.org/10.3389/fimmu.2022.874792
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