bims-rimeca Biomed News
on RNA methylation in cancer
Issue of 2022–03–06
eight papers selected by
Sk Ramiz Islam, Saha Institute of Nuclear Physics
  1. AS3MT facilitates NLRP3 inflammasome activation by m6A modification during arsenic-induced hepatic insulin resistance.
  2. The expression of m6A regulators correlated with the immune microenvironment plays an important role in the prognosis of pancreatic ductal adenocarcinoma.
  3. Links Between N 6-Methyladenosine and Tumor Microenvironments in Colorectal Cancer.
  4. YTHDF1 promotes intrahepatic cholangiocarcinoma progression via regulating EGFR mRNA translation.
  5. m1A methylation modification patterns and metabolic characteristics in hepatocellular carcinoma.
  6. RNA modification "writer"-mediated RNA modification patterns and tumor microenvironment characteristics of cervical cancer.
  7. Two zinc finger proteins with functions in m6A writing interact with HAKAI.
  8. LXA4 enhances prostate cancer progression by facilitating M2 macrophage polarization via inhibition of METTL3.
  1. Cell Biol Toxicol. 2022 Feb 28.
    AS3MT facilitates NLRP3 inflammasome activation by m6A modification during arsenic-induced hepatic insulin resistance.
    Tianming Qiu, Chenbing Wu, Xiaofeng Yao, Qiuyue Han, Ningning Wang, Weizhuo Yuan, Jingyuan Zhang, Yan Shi, Liping Jiang, Xiaofang Liu, Guang Yang, Xiance Sun.
      N6-methyladenosine (m6A) messenger RNA methylation is the most widespread gene regulatory mechanism affecting liver functions and disorders. However, the relationship between m6A methylation and arsenic-induced hepatic insulin resistance (IR), which is a critical initiating event in arsenic-induced metabolic syndromes such as type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD), remains unclear. Here, we showed that arsenic treatment facilitated methyltransferase-like 14 (METTL14)-mediated m6A methylation, and that METTL14 interference reversed arsenic-impaired hepatic insulin sensitivity. We previously showed that arsenic-induced NOD-like receptor protein 3 (NLRP3) inflammasome activation contributed to hepatic IR. However, the regulatory mechanisms underlying the role of arsenic toward the post-transcriptional modification of NLRP3 remain unclear. Here, we showed that NLRP3 mRNA stability was enhanced by METTL14-mediated m6A methylation during arsenic-induced hepatic IR. Furthermore, we demonstrated that arsenite methyltransferase (AS3MT), an essential enzyme in arsenic metabolic processes, interacted with NLRP3 to activate the inflammasome, thereby contributing to arsenic-induced hepatic IR. Also, AS3MT strengthened the m6A methylase association with NLRP3 to stabilize m6A-modified NLRP3. In summary, we showed that AS3MT-induced m6A modification critically regulated NLRP3 inflammasome activation during arsenic-induced hepatic IR, and we identified a novel post-transcriptional function of AS3MT in promoting arsenicosis.
    Keywords:  AS3MT; Arsenic; Inflammasome; Insulin resistance; m6A methylation
    DOI:  https://doi.org/10.1007/s10565-022-09703-7
  2. Gland Surg. 2022 Jan;11(1): 147-165
    The expression of m6A regulators correlated with the immune microenvironment plays an important role in the prognosis of pancreatic ductal adenocarcinoma.
    Yutong Yao, Le Luo, Guangming Xiang, Junjie Xiong, Nengwen Ke, Chunlu Tan, Yonghua Chen, Xubao Liu.
       Background: The relationship between N6-methyladenosine (m6A) RNA methylation regulators and the tumor immune microenvironment has been extensively studied. Nevertheless, the potential function of m6A regulators in the tumor immune landscape of pancreatic ductal adenocarcinoma (PDAC) remains to be fully elucidated.
    Methods: Here, we systematically evaluated the expression of 19 m6A regulators in PDAC patients from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) database. Utilizing consensus clustering, the PDAC patients were segmented into two subgroups according to the expression of 19 m6A regulators. A prognostic risk signature of 5 m6A methylation regulators (ALKBH5, IGF2BP2, IGF2BP3, LRPPRC, and KIAA1429) was then built, and the PDAC patients were divided into high-risk and low-risk groups. Subsequently, differences in independent prognostic parameters, risk score distribution, survival, and cluster analysis between high-risk and low-risk groups were analyzed.
    Results: We found two subgroups with dramatically different immune landscapes and prognoses. Subsequently, differences in independent prognostic parameters, risk score distribution, survival, and cluster analysis between the high-risk and low-risk groups were found. Moreover, these gene signatures displayed good discriminative performances in the GEO datasets. We also found that the risk score was positively correlated with the tumor mutation burden (TMB), and the TMB value was higher in the high-risk scoring group. The low-risk scoring group was linked by a stronger response to anti-programmed cell death ligand 1 (anti-PD-L1) immunotherapy and clinical advantages in the immunotherapeutic advanced urothelial cancer (IMvigor210) cohort. Ultimately, we found that these 5 m6A regulators had a fatal regulatory role on the tumor immune microenvironment in PDAC patients.
    Conclusions: The construction signature based on the m6A regulators may be crucial regulators of the tumor immune microenvironment in PDAC, providing a new approach to improving the immunotherapy strategy for PDAC patients.
    Keywords:  Pancreatic ductal adenocarcinoma (PDAC); consensus clustering; m6A methylation regulators; overall survival; tumor immune microenvironment
    DOI:  https://doi.org/10.21037/gs-21-859
  3. Front Cell Dev Biol. 2022 ;10 807129
    Links Between N 6-Methyladenosine and Tumor Microenvironments in Colorectal Cancer.
    Yundi Zhang, Ke Zhang, Haoming Gong, Qin Li, Lajie Man, Qingchang Jin, Lin Zhang, Song Li.
      N6-methyladenosine (m6A) is a critical epigenetic modification for tumor malignancies, but its role in regulating the tumor microenvironments (TMEs) has not been fully studied. By integrating multiple data sets and multi-omics data, we comprehensively evaluated the m6A "writers," "erasers," and "readers" in colorectal cancer and their association with TME characteristics. The m6A regulator genes showed specific patterns in co-mutation, copy number variation, and expression. Based on the transcriptomic data of the m6A regulators and their correlated genes, two types of subtyping systems, m6AregCluster and m6AsigCluster, were developed. The clusters were distinct in pathways (metabolism/inflammation/extracellular matrix and interaction), immune phenotypes (immune-excluded/immune-inflamed/immune-suppressive), TME cell composition (lack immune and stromal cells/activated immune cells/stromal and immune-suppressive cells), stroma activities, and survival outcomes. We also established an m6Ascore associated with molecular subgroups, microsatellite instability, DNA repair status, mutation burdens, and survival and predicted immunotherapy outcomes. In conclusion, our work revealed a close association between m6A modification and TME formation. Evaluating m6A in cancer has helped us comprehend the TME status, and targeting m6A in tumor cells might help modulate the TME and improve tumor therapy and immunotherapy.
    Keywords:  N6-methyladenosine; colorectal cancer; immunotherapy; molecular classification; tumor microenvironments
    DOI:  https://doi.org/10.3389/fcell.2022.807129
  4. J Gastroenterol Hepatol. 2022 Mar 01.
    YTHDF1 promotes intrahepatic cholangiocarcinoma progression via regulating EGFR mRNA translation.
    Xiang Huang, Lefan Zhu, Lina Wang, Wenjie Huang, Li Tan, Haining Liu, Jihui Huo, Tianhong Su, Mengping Zhang, Ming Kuang, Xiaoxing Li, Zihao Dai, Lixia Xu.
       BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive disease with the underlying mechanisms poorly understood. YTHDF1, an m6 A reader protein, has important physiological functions in regulation of tumor development. However, the effect of YTHDF1 on ICC progression remains unknown yet.
    METHODS: The expression level of YTHDF1 in human ICC tissue was examined in the Cancer Genome Atlas (TCGA) database and our cohort. The role of YTHDF1 was detected using two human ICC cell lines in vitro. An ICC tumorigenesis mouse model was established via hydrodynamic transfection of AKT/YAP plasmids. m6 A sequencing (m6 A-seq), RNA immunoprecipitation sequencing (RIP-seq), and RNA-seq were carried out to explore the mechanism of YTHDF1 modulating ICC progression.
    RESULTS: Here we find that YTHDF1 is up-regulated in ICC and associated with shorter survival of ICC patients. Depletion of YTHDF1 inhibits cell proliferation, cell migration and invasion, while overexpression of wild type YTHDF1, but not m6 A reader domain mutant YTHDF1, significantly enhances tumor cell growth and aggressive abilities in vitro. Moreover, overexpression of YTHDF1 promotes the AKT/YAP transfection-induced orthotopic ICC tumorigenesis and progression in vivo. Mechanistically, we identify that YTHDF1 regulates the translation of epidermal growth factor receptor (EGFR) mRNA via binding m6 A sites in the 3'-UTR of EGFR transcript, thus leading to aberrant activities of downstream signal pathways that impact tumor progression.
    CONCLUSION: Our data uncover the oncogenic function and m6 A reader-dependent mechanism of YTHDF1 in regulation of ICC progression. Restricting abnormal oncogenic mRNA translation by targeting YTHDF1 may be a novel and promising strategy for ICC treatment.
    Keywords:  EGFR; Intrahepatic cholangiocarcinoma; YTHDF1; m6A modification; mRNA translation
    DOI:  https://doi.org/10.1111/jgh.15816
  5. BMC Gastroenterol. 2022 Mar 03. 22(1): 93
    m1A methylation modification patterns and metabolic characteristics in hepatocellular carcinoma.
    Chengcheng Tong, Wei Wang, Chiyi He.
       BACKGROUND: The dysregulation of RNA methylation has been demonstrated to contribute to tumorigenicity and progression in recent years. However, the alteration of N1-methyladenosine (m1A) methylation and its role in hepatocellular carcinoma (HCC) remain unclear.
    METHODS: We systematically investigated the modification patterns of 10 m1A regulators in HCC samples and evaluated the metabolic characteristics of each pattern. A scoring system named the m1Ascore was developed using principal component analysis. The clinical value of the m1Ascore in risk stratification and drug screening was further explored.
    RESULTS: Three m1A modification patterns with distinct metabolic characteristics were identified, corresponding to the metabolism-high, metabolism-intermediate and metabolism-excluded phenotypes. Patients were divided into high- or low-m1Ascore groups, and a significant survival difference was observed. External validation confirmed the prognostic value of the m1Ascore. A nomogram incorporating the m1Ascore and other clinicopathological factors was constructed and had good performance for predicting survival. Two agents, mitoxantrone and doxorubicin, were determined to be potential therapeutic drugs for the high-risk group.
    CONCLUSION: This study provided novel insights into m1A modification and metabolic heterogeneity in cancer, promoted risk stratification in the clinic from the perspective of m1A modification, and further guided individual treatment strategies.
    Keywords:  Hepatocellular carcinoma; Metabolism; Prognosis; m1A
    DOI:  https://doi.org/10.1186/s12876-022-02160-w
  6. Clin Transl Oncol. 2022 Feb 27.
    RNA modification "writer"-mediated RNA modification patterns and tumor microenvironment characteristics of cervical cancer.
    Yanjun Qu, Hong Zhu, Congcong Kong, Xin Zheng, Dejun Wang, Xiuwei Chen, Dandan Yuan.
       PURPOSE: As an epigenetic regulation mechanism after transcription, RNA modification is installed by endogenous "writer" enzymes and is widely involved in a variety of physiological processes, including cancer progression. This study explored the RNA modification patterns of cervical cancer to clarify overall effect of RNA modification on tumor microenvironment (TME) characteristics and immune/targeted therapy.
    METHODS: 26 RNA modification "writers" were clustered, and the RNA modification patterns and TME characteristics of cervical cancer patients in TCGA were systematically evaluated. Based on differentially expressed genes (DEGs) between different RNA modification patterns, an RNA modification "writer" score (WM score) system was developed to assess the RNA modification of a single sample.
    RESULTS: Two different RNA modification patterns of cervical cancer were identified, and these patterns were significantly related to the prognosis and TME infiltration characteristics of patients. WM score was an independent risk factor for the prognosis of cervical cancer. High WM score was characterized by poor prognosis, low immune infiltration and low tumor mutation burden (TMB), while low-WM score was related to relatively long overall survival (OS), more immune components in TME and increased TMB. In addition, the low-WM score group was expected to be more sensitive to programmed cell death protein 1 (PD-1) therapy and showed lower predicted IC50 of chemotherapy drugs paclitaxel and cisplatin treatment.
    CONCLUSIONS: This study identified and characterized RNA modification patterns, and clarified potential relationship between RNA modification patterns and immune infiltration characteristics and immunotherapy of cervical cancer, offering a new evaluation scheme for treatment of cervical cancer patients.
    Keywords:  Cervical cancer; Immunotherapy; RNA modification “writers”; Tumor microenvironment; WM score
    DOI:  https://doi.org/10.1007/s12094-022-02787-x
  7. Nat Commun. 2022 Mar 02. 13(1): 1127
    Two zinc finger proteins with functions in m6A writing interact with HAKAI.
    Mi Zhang, Zsuzsanna Bodi, Katarzyna Mackinnon, Silin Zhong, Nathan Archer, Nigel P Mongan, Gordon G Simpson, Rupert G Fray.
      The methyltransferase complex (m6A writer), which catalyzes the deposition of N6-methyladenosine (m6A) in mRNAs, is highly conserved across most eukaryotic organisms, but its components and interactions between them are still far from fully understood. Here, using in vivo interaction proteomics, two HAKAI-interacting zinc finger proteins, HIZ1 and HIZ2, are discovered as components of the Arabidopsis m6A writer complex. HAKAI is required for the interaction between HIZ1 and MTA (mRNA adenosine methylase A). Whilst HIZ1 knockout plants have normal levels of m6A, plants in which it is overexpressed show reduced methylation and decreased lateral root formation. Mutant plants lacking HIZ2 are viable but have an 85% reduction in m6A abundance and show severe developmental defects. Our findings suggest that HIZ2 is likely the plant equivalent of ZC3H13 (Flacc) of the metazoan m6A-METTL Associated Complex.
    DOI:  https://doi.org/10.1038/s41467-022-28753-3
  8. Int Immunopharmacol. 2022 Feb 25. pii: S1567-5769(22)00070-4. [Epub ahead of print]107 108586
    LXA4 enhances prostate cancer progression by facilitating M2 macrophage polarization via inhibition of METTL3.
    Gaozhen Jia, Xingjie Wang, Wenbo Wu, Yu Zhang, Shaoan Chen, Jing Zhao, Wei Zhao, Weiguo Li, Xiaowen Sun, Bangmin Han.
      Tumor-associated macrophages (TAMs) are major innate immune cells that play crucial roles in prostate cancer onset and progression. Recently, increasing evidence has suggested that elevated N6-adenine methylation of mRNA is observed in prostate cancer tissues and is closely associated with a poor prognosis. However, its role in prostate cancer-associated macrophages remains poorly understood. Here, we showed that downregulation of METTL3 in prostate cancer TAMs modulated macrophages toward an M2-like phenotype and that this modulation was mediated by activation of STAT6. In addition, our data demonstrated that prostate cancer cell-derived small lipid molecule lipoxin A4 (LXA4) activated STAT6 by inhibiting METTL3. Treatment with PBP10 (an inhibitor of the LXA4 receptor) abolished the inhibition of METTL3 by LXA4 and consequently reduced the tumorigenicity of prostate cancer cells. Altogether, this work demonstrated that prostate cancer cells facilitate polarization of M2 like macrophages by releasing LXA4 via inhibiting METTL3. These findings provide new insight into the mechanism of microenvironmental regulation of macrophage polarization during prostate cancer progression.
    Keywords:  LXA4; METTL3; Macrophages; Prostate cancer; STAT6
    DOI:  https://doi.org/10.1016/j.intimp.2022.108586
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