bims-rimeca Biomed News
on RNA methylation in cancer
Issue of 2022–08–07
nine papers selected by
Sk Ramiz Islam, Saha Institute of Nuclear Physics
  1. IGF2BP2 promotes pancreatic carcinoma progression by enhancing the stability of B3GNT6 mRNA via m6A methylation.
  2. METTL14-dependent m6A modification controls iNKT cell development and function.
  3. Mettl3-mediated mRNA m6A modification controls postnatal liver development by modulating the transcription factor Hnf4a.
  4. The m6A methyltransferase Mettl3 deficiency attenuates hepatic stellate cell activation and liver fibrosis.
  5. Inhibition of the m6A reader IGF2BP2 as a strategy against T-cell acute lymphoblastic leukemia.
  6. N6-Methyladenosine Reader YTHDF2 Enhances Non-Small-Cell Lung Cancer Cell Proliferation and Metastasis through Mediating circ_SFMBT2 Degradation.
  7. N6-adenomethylation of GsdmC is essential for Lgr5+ stem cell survival to maintain normal colonic epithelial morphogenesis.
  8. FOXA1 inhibits hypoxia programs through transcriptional repression of HIF1A.
  9. METTL3 preferentially enhances non-m6A translation of epigenetic factors and promotes tumourigenesis.
  1. Cancer Med. 2022 Jul 31.
    IGF2BP2 promotes pancreatic carcinoma progression by enhancing the stability of B3GNT6 mRNA via m6A methylation.
    Pei Cao, Yufan Wu, Ding Sun, Weigang Zhang, Junyi Qiu, Zuxiong Tang, Xiaofeng Xue, Lei Qin.
       BACKGROUND: Pancreatic carcinoma (PC) is a highly lethal cancer with an increasing mortality rate, its five-year survival rate is only approximately 4%. N6-methyladenosine (m6A) modification is the most common posttranscriptional modification of RNA, it could affect tumor formation by regulating m6A modifications in the mRNA of key oncogenes or tumor suppressor genes. However, its role in PC remains unclear.
    METHODS: We combined bioinformatic analysis with in vitro and in vivo experiments to investigate the expression profile of methylation modulators and identify key m6A regulators in the progression of PC. Further study focused on exploring the target genes binding to the regulators through RIP and immunofluorescence staining experiment.
    RESULTS: TCGA and Gene Expression Omnibus (GEO) analyses revealed an overall increasing trend in the expression of m6A regulators in PC, and consensus clustering analysis of m6A modification showed that the expression of regulators was negatively correlated with the survival rate. LASSO-Cox regression analysis revealed that IGF2BP2, METTL3, ALKBH5 and KIAA1429 were associated with hazard ratios (HR), but only IGF2BP2 was sufficiently appropriate for the m6A survival prognosis model. The IHC and WB results verified high protein expression of IGF2BP2 in PC, and IGF2BP2 knockdown inhibited the proliferation and migration of PC cells. We predicted and verified B3GNT6 was observably regulated by IGF2BP2 via RIP assays. In addition, IF staining confirmed the co-expression of IGF2BP2 and B3GNT6. The tumor-promoting effect of IGF2BP2 and its co-expression with B3GNT6 were verified in an animal model.
    CONCLUSIONS: Elevated m6A levels promote PC progression. IGF2BP2 is a credible marker and modulates B3GNT6 mRNA stability, indicating that IGF2BP2 is a potential prognostic marker and therapeutic target in PC progression.
    Keywords:  B3GNT6; IGF2BP2; RNA methylation; epigenetic modification; pancreatic carcinoma
    DOI:  https://doi.org/10.1002/cam4.5096
  2. Cell Rep. 2022 Aug 02. pii: S2211-1247(22)00965-2. [Epub ahead of print]40(5): 111156
    METTL14-dependent m6A modification controls iNKT cell development and function.
    Liang Cao, Eva Morgun, Samantha Genardi, Lavanya Visvabharathy, Yongyong Cui, Haochu Huang, Chyung-Ru Wang.
      N6-methyladenosine (m6A), the most common form of RNA modification, controls CD4+ T cell homeostasis by targeting the IL-7/STAT5/SOCS signaling pathways. The role of m6A modification in unconventional T cell development remains unknown. Using mice with T cell-specific deletion of RNA methyltransferase METTL14 (T-Mettl14-/-), we demonstrate that m6A modification is indispensable for iNKT cell homeostasis. Loss of METTL14-dependent m6A modification leads to the upregulation of apoptosis in double-positive thymocytes, which in turn decreases Vα14-Jα18 gene rearrangements, resulting in drastic reduction of iNKT numbers in the thymus and periphery. Residual T-Mettl14-/- iNKT cells exhibit increased apoptosis, impaired maturation, and decreased responsiveness to IL-2/IL-15 and TCR stimulation. Furthermore, METTL14 knockdown in mature iNKT cells diminishes their cytokine production, correlating with increased Cish expression and decreased TCR signaling. Collectively, our study highlights a critical role for METTL14-dependent-m6A modification in iNKT cell development and function.
    Keywords:  CD1; CP: Immunology; CP: Molecular biology; NKT cells; T cell development; knockout mice; m(6)A
    DOI:  https://doi.org/10.1016/j.celrep.2022.111156
  3. Nat Commun. 2022 Aug 05. 13(1): 4555
    Mettl3-mediated mRNA m6A modification controls postnatal liver development by modulating the transcription factor Hnf4a.
    Yan Xu, Zhuowei Zhou, Xinmei Kang, Lijie Pan, Chang Liu, Xiaoqi Liang, Jiajie Chu, Shuai Dong, Yanli Li, Qiuli Liu, Yuetong Sun, Shanshan Yu, Qi Zhang.
      Hepatic specification and functional maturation are tightly controlled throughout development. N6-methyladenosine (m6A) is the most abundant RNA modification of eukaryotic mRNAs and is involved in various physiological and pathological processes. However, the function of m6A in liver development remains elusive. Here we dissect the role of Mettl3-mediated m6A modification in postnatal liver development and homeostasis. Knocking out Mettl3 perinatally with Alb-Cre (Mettl3 cKO) induces apoptosis and steatosis of hepatocytes, results in severe liver injury, and finally leads to postnatal lethality within 7 weeks. m6A-RIP sequencing and RNA-sequencing reveal that mRNAs of a series of crucial liver-enriched transcription factors are modified by m6A, including Hnf4a, a master regulator for hepatic parenchymal formation. Deleting Mettl3 reduces m6A modification on Hnf4a, decreases its transcript stability in an Igf2bp1-dependent manner, and down-regulates Hnf4a expression, while overexpressing Hnf4a with AAV8 alleviates the liver injury and prolongs the lifespan of Mettl3 cKO mice. However, knocking out Mettl3 in adults using Alb-CreERT2 does not affect liver homeostasis. Our study identifies a dynamic role of Mettl3-mediated RNA m6A modification in liver development.
    DOI:  https://doi.org/10.1038/s41467-022-32169-4
  4. Mol Ther. 2022 Aug 02. pii: S1525-0016(22)00441-5. [Epub ahead of print]
    The m6A methyltransferase Mettl3 deficiency attenuates hepatic stellate cell activation and liver fibrosis.
    Yanli Li, Xinmei Kang, Zhuowei Zhou, Lijie Pan, Huaxin Chen, Xiaoqi Liang, Jiajie Chu, Shuai Dong, Chang Liu, Shanshan Yu, Dan Tu, Yiwang Zhang, Mian Ge, Wenjie Chen, Yan Xu, Qi Zhang.
      Activation of hepatic stellate cells (HSCs) is a central driver of liver fibrosis. Previous investigations have identified various altered epigenetic landscapes during the cellular progression of HSC activation. N6-methyladenosine (m6A) is the most abundant internal RNA modification in eukaryotic cells and is dynamically regulated under various physiological and pathophysiological conditions. However, the functional role of Mettl3-mediated m6A in liver fibrosis remains elusive. Here, we found that the HSC-specific knockout of m6A methyltransferase Mettl3 suppressed HSC activation and significantly alleviated liver fibrosis. Multi-omics analysis of HSCs showed that Mettl3 depletion reduced m6A deposition on mRNA transcripts of Lats2 (a central player of the Hippo/YAP signaling pathway) and slowed down their degradation. Elevated Lats2 increased phosphorylation of downstream transcription factor YAP, suppressed YAP nuclear translocation, and decreased pro-fibrotic gene expression. Overexpressing YAP mutant resistant to phosphorylation by Lats2 partially rescued the activation and pro-fibrotic gene expression of Mettl3-deficient HSCs. Our study revealed that disruption of Mettl3 in HSCs mitigated liver fibrosis by controlling the Hippo/YAP signaling pathway, providing potential therapeutic strategies to alleviate liver fibrosis by targeting epitranscriptomic machinery.
    Keywords:  Hepatic stellate cells (HSCs); Hippo/YAP; LATS2; Liver fibrosis; N6-methyladenosine (m(6)A)
    DOI:  https://doi.org/10.1016/j.ymthe.2022.07.020
  5. Leukemia. 2022 Aug 01.
    Inhibition of the m6A reader IGF2BP2 as a strategy against T-cell acute lymphoblastic leukemia.
    Panpan Feng, Dawei Chen, Xia Wang, Yanxia Li, Zhenyu Li, Boya Li, Yupeng Zhang, Wei Li, Jingru Zhang, Jingjing Ye, Baobing Zhao, Jingxin Li, Chunyan Ji.
      T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignant leukemia with extremely limited treatment for relapsed patients. N6-methyladenosine (m6A) reader insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) participates in the initiation and growth of cancers by communicating with various targets. Here, we found IGF2BP2 was highly expressed in T-ALL. Gain and loss of IGF2BP2 demonstrated IGF2BP2 was essential for T-ALL cell proliferation in vitro and loss of IGF2BP2 prolonged animal survival in a human T-ALL xenograft model. Mechanistically, IGF2BP2 directly bound to T-ALL oncogene NOTCH1 via an m6A dependent manner. Furthermore, we identified a small-molecule IGF2BP2 inhibitor JX5 and treatment of T-ALL with JX5 showed similar functions as knockdown of IGF2BP2. These findings not only shed light on the role of IGF2BP2 in T-ALL, but also provide an alternative γ‑Secretase inhibitors (GSI) therapy to treat T-ALL.
    DOI:  https://doi.org/10.1038/s41375-022-01651-9
  6. Contrast Media Mol Imaging. 2022 ;2022 1087622
    N6-Methyladenosine Reader YTHDF2 Enhances Non-Small-Cell Lung Cancer Cell Proliferation and Metastasis through Mediating circ_SFMBT2 Degradation.
    Jing Xu, Yan Shang, Xiong Qin, Yun Gai, Feng Cai, Hua Xiao, Chen Zhou, Youhui Fu, Xiahui Ge.
       Objective: circ_SFMBT2 was reported to facilitate malignant progression in various cancers, but its function in non-small-cell lung cancer (NSCLC) has not been fully uncovered. This study aimed to investigate the effects of N6-methyladenosine (m6A) methylation of circ_SFMBT2 (circ_0017628) on non-small-cell lung cancer (NSCLC) and its underlying mechanisms.
    Methods: Paired tumor and noncancerous tissues from NSCLC patients were surgically collected from January 2020 to March 2021 in our hospital. The levels of circ_SFMBT2 and LATS2 in NSCLC and human bronchial epithelial cells were assayed with qRT-PCR. Overexpression or silencing of circ_SFMBT2, LATS2, or YTHDF2 was performed in the NSCLC cells. CCK-8, colony-forming, and transwell assays were performed to analyze cell proliferation, viability, and migration, respectively. Meanwhile, the expression of MMP-9, E-cadherin, vimentin, and the Hippo/YAP pathway components was examined by western blotting. The m6A enrichment in circ_SFMBT2 was verified using methylated RNA immunoprecipitation, and interaction between circ_SFMBT2 and YTHDF2 was assessed by RNA pull-down and immunoprecipitation assays.
    Results: Both circ_SFMBT2 and LATS2 were lowly expressed in NSCLC cells and tissues. A positive correlation of circ_SFMBT2 with LATS2 was identified, and circ_SFMBT2 was localized predominantly in the cytoplasm. circ_SFMBT2 overexpression negatively regulated cell proliferation, viability, migration, and epithelial-mesenchymal transition while promoting the Hippo/YAP pathway activation. Notably, knockdown of LATS2 effectively abrogated the inhibitory effects of circ_SFMBT2 overexpression on NSCLC cell malignancies. Besides, m6A was specifically enriched in circ_SFMBT2, and circ_SFMBT2 could bind to YTHDF2. Silencing of YTHDF2 led to an increase in circ_SFMBT2 expression while inhibiting the malignancy of cancer cells.
    Conclusion: Our results showed that YTHDF2 could facilitate NSCLC cell proliferation and metastasis via the Hippo/YAP pathway activation by mediating circ_SFMBT2 degradation.
    DOI:  https://doi.org/10.1155/2022/1087622
  7. Dev Cell. 2022 Aug 01. pii: S1534-5807(22)00495-6. [Epub ahead of print]
    N6-adenomethylation of GsdmC is essential for Lgr5+ stem cell survival to maintain normal colonic epithelial morphogenesis.
    Jie Du, Rajesh Sarkar, Yan Li, Lei He, Wenjun Kang, Wang Liao, Weicheng Liu, Tivoli Nguyen, Linda Zhang, Zifeng Deng, Urszula Dougherty, Sonia S Kupfer, Mengjie Chen, Joel Pekow, Marc Bissonnette, Chuan He, Yan Chun Li.
      Gut epithelial morphogenesis is maintained by intestinal stem cells. Here, we report that depletion of N6-adenosine methyltransferase subunit Mettl14 from gut epithelial cells in mice impaired colon mucosal morphogenesis, leading to increased mucosal permeability, severe inflammation, growth retardation, and premature death. Mettl14 ablation triggered apoptosis that depleted Lgr5+ stem cells and disrupted colonic organoid growth and differentiation, whereas the inhibition of apoptosis rescued Mettl14-deleted mice and organoids. Mettl14 depletion disrupted N6-adenomethylation on GsdmC transcripts and abolished GsdmC expression. Reconstitution of Mettl14-deleted organoids or mice with GSDMC rescued Lgr5 expression and prevented apoptosis and mouse premature death, whereas GSDMC silence eliminated LGR5 and triggered apoptosis in human colonic organoids and epithelial cells. Mechanistically, Mettl14 depletion eliminated mitochondrial GsdmC, disrupted mitochondrial membrane potential, and triggered cytochrome c release that activates the pro-apoptotic pathway. In conclusion, GsdmC N6-adenomethylation protects mitochondrial homeostasis and is essential for Lgr5+ cell survival to maintain normal colonic epithelial regeneration.
    Keywords:  Apoptosis; Clu; Colonic epithelium; GsdmC; Intestinal stem cell; Lgr5; Mettl14; Mitochondria; m(6)A
    DOI:  https://doi.org/10.1016/j.devcel.2022.07.006
  8. Oncogene. 2022 Aug 05.
    FOXA1 inhibits hypoxia programs through transcriptional repression of HIF1A.
    Xiaohai Wang, Lourdes Brea, Xiaodong Lu, Galina Gritsina, Su H Park, Wanqing Xie, Jonathan C Zhao, Jindan Yu.
      Intratumoral hypoxia is associated with castration-resistant prostate cancer (CRPC), a lethal disease. FOXA1 is an epithelial transcription factor that is down-regulated in CRPC. We have previously reported that FOXA1 loss induces epithelial-mesenchymal transition (EMT) and cell motility through elevated TGFβ signaling. However, whether FOXA1 directly regulates hypoxia pathways of CRPC tumors has not been previously studied. Here we report that FOXA1 down-regulation induces hypoxia transcriptional programs, and FOXA1 level is negatively correlated with hypoxia markers in clinical prostate cancer (PCa) samples. Mechanistically, FOXA1 directly binds to an intragenic enhancer of HIF1A to inhibit its expression, and HIF1A, in turn, is critical in mediating FOXA1 loss-induced hypoxia gene expression. Further, we identify CCL2, a chemokine ligand that modulates tumor microenvironment and promotes cancer progression, as a crucial target of the FOXA1-HIF1A axis. We found that FOXA1 loss leads to immunosuppressive macrophage infiltration and increased cell invasion, dependent on HIF1A expression. Critically, therapeutic targeting of HIF1A-CCL2 using pharmacological inhibitors abolishes FOXA1 loss-induced macrophage infiltration and PCa cell invasion. In summary, our study reveals an essential role of FOXA1 in controlling the hypoxic tumor microenvironment and establishes the HIF1A-CCL2 axis as one mechanism of FOXA1 loss-induced CRPC progression.
    DOI:  https://doi.org/10.1038/s41388-022-02423-6
  9. Nat Cell Biol. 2022 Aug 04.
    METTL3 preferentially enhances non-m6A translation of epigenetic factors and promotes tumourigenesis.
    Xueju Wei, Yue Huo, Jingnan Pi, Yufeng Gao, Shuan Rao, Manman He, Qinglv Wei, Peng Song, Yiying Chen, Dongxu Lu, Wei Song, Junbo Liang, Lingjie Xu, Haixia Wang, Guolin Hong, Yuehong Guo, Yanmin Si, Jiayue Xu, Xiaoshuang Wang, Yanni Ma, Shuyang Yu, Dongling Zou, Jing Jin, Fang Wang, Jia Yu.
      METTL3 encodes the predominant catalytic enzyme to promote m6A methylation in nucleus. Recently, accumulating evidence has shown the expression of METTL3 in cytoplasm, but its function is not fully understood. Here we demonstrated an m6A-independent mechanism for METTL3 to promote tumour progression. In gastric cancer, METTL3 could not only facilitate cancer progression via m6A modification, but also bind to numerous non-m6A-modified mRNAs, suggesting an unexpected role of METTL3. Mechanistically, cytoplasm-anchored METTL3 interacted with PABPC1 to stabilize its association with cap-binding complex eIF4F, which preferentially promoted the translation of epigenetic factors without m6A modification. Clinical investigation showed that cytoplasmic distributed METTL3 was highly correlated with gastric cancer progression, and this finding could be expanded to prostate cancer. Therefore, the cytoplasmic METTL3 enhances the translation of epigenetic mRNAs, thus serving as an oncogenic driver in cancer progression, and METTL3 subcellular distribution can assist diagnosis and predict prognosis for patients with cancer.
    DOI:  https://doi.org/10.1038/s41556-022-00968-y
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