bims-rimeca 2023-12-03 papers

bims-rimeca

Biomed News

on RNA methylation in cancer

Issue of 2023–12–03
eight papers selected by
Sk Ramiz Islam, Saha Institute of Nuclear Physics

Research progress of N6-methyladenosine in colorectal cancer: A review.
N6-Methyladenosine Methylation of mRNA in Cell Apoptosis.
Pan-cancer analysis reveals the pro-oncogenic role of N6-methyladenosine (m6A)-regulated NTMT1 in head and neck squamous cell carcinoma.
Methyltransferase-like 3-mediated m6A modification of miR-1908-5p contributes to nasopharyngeal carcinoma progression by targeting homeodomain-only protein homeobox.
Long non-coding RNA linc00659 promotes tumour progression by regulating FZD6/Wnt/β-catenin signalling pathway in colorectal cancer via m6A reader IGF2BP1.
IGF2BP2 attenuates intestinal epithelial cell ferroptosis in colitis by stabilizing m6A-modified GPX4 mRNA.
m6A modification negatively regulates translation by switching mRNA from polysome to P-body via IGF2BP3.
Therapeutic effect and transcriptome-methylome characteristics of METTL3 inhibition in liver hepatocellular carcinoma.

Medicine (Baltimore). 2023 Nov 24. 102(47): e36394

Research progress of N6-methyladenosine in colorectal cancer: A review.

Yu Lin, Hongjun Shi, Lianping Wu, Linyang Ge, Zengqing Ma.

Colorectal cancer is the third most common malignant tumor worldwide, causing serious harm to human health. Epigenetic modification, especially RNA methylation modification, plays a critical role in the occurrence and development of colorectal cancer via post-transcriptional regulation of mRNA and non-coding RNA expression. Among these, N6-methyladenosine (m6A) is the most common chemical modification in mammals, which plays an important role in the progress of cancer, including colorectal cancer. m6A is a dynamic and reversible process and is mainly regulated by m6A methyltransferase ("writers"), m6A demethylases ("erasers"), and m6A binding proteins ("readers"). Herein, we reviewed recent advances in the role of m6A modification in colorectal cancer and focused on the factors affecting m6A modification. Furthermore, we discussed the clinical application of m6A modifications for colorectal cancer diagnosis, prognosis, and treatment and provided guides in clinical practice. m6A modification and m6A regulators play significant roles in the occurrence and development of colorectal cancer by regulating the stability and translation of mRNAs, the maturation of miRNAs, and the function of lncRNAs. m6A regulators can play biological roles in colorectal cancer through m6A-dependent manner or m6A-independent manner. Multiplies of internal factors, including miRNAs and lncRNAs, and external factors can also regulate the m6A modification by completing with m6A regulators in a base complement manner, regulating the expression of m6A and mutating the m6A site. m6A regulators and m6A modificantion are diagnostic and prognostic markers for CRC. Therefore, m6A regulators and m6A modificantion may be potential therapeutic target for CRC in the future.

DOI: https://doi.org/10.1097/MD.0000000000036394
Mol Neurobiol. 2023 Dec 02.

N6-Methyladenosine Methylation of mRNA in Cell Apoptosis.

Lin Zhang, Jian Xia.

  Apoptosis, a highly controlled homeostatic mechanism that eliminates single cells without destroying tissue function, occurs during growing development and senescence. N6-methyladenosine (m6A), as the most common internal modification of eukaryotic mRNA, fine-tunes gene expression by regulating many aspects of mRNA metabolism, such as splicing, nucleation, stability, translation, and degradation. Remarkably, recent reports have indicated that aberrant methylation of m6A-related RNA may directly or indirectly influence the expression of apoptosis-related genes, thus regulating the process of cell apoptosis. In this review, we summarized the relationship between m6A modification and cell apoptosis, especially its role in the nervous system, and analyzed the limitations of the current research. Pro-apoptotic protein, anti-apoptotic protein, pro-survival protein, and caspases participate in different processes of apoptosis. METTL3 and METTL14 directly regulate the expression of Bcl-2, Bcl-xl, Bak, Bax, caspase7, caspase3, MYB, and MYC. WTAP, FTO, ALKBH5, YTHDF2, and eIF3 can also control cell apoptosis by regulating the expression of certain genes.

Keywords:  Cell apoptosis; N6-methyladenosine methylation; mRNAs

DOI:  https://doi.org/10.1007/s12035-023-03813-x
J Biochem Mol Toxicol. 2023 Nov 28. e23603

Pan-cancer analysis reveals the pro-oncogenic role of N6-methyladenosine (m6A)-regulated NTMT1 in head and neck squamous cell carcinoma.

Chunhong Zhao, Min Yu, Yujie Li.

  Head and neck squamous cell carcinoma (HNSC) is a common and fatal tumor with a bleak prognosis, posing a significant threat to human health. N6-methyladenosine (m6A) modification regulates tumor progression by modulating gene expression post-transcriptionally. Nevertheless, the specific function of m6A-modified tumor drivers in HNSC remains largely uncharted. In this study, we revealed the pro-oncogenic role of m6A-regulated NTMT1 in HNSC through comprehensive pan-cancer analysis and experimental validation. By scrutinizing the prognostic and expression profiles of NTMT1 across over 30 cancer types, we observed a significant association between NTMT1 and patient overall survival in ACC, HNSC, LAML, LGG, KIRC, and STAD. Moreover, we find a close correlation between NTMT1 and disease-free survival in ACC, HNSC, LUSC, UVM, KIRC, and STAD. NTMT1 exhibited dysregulation in 15 cancers, including CESC, CHOL, COAD, DLBC, GBM, HNSC, LGG, LIHC, PAAD, READ, SKCM, THYM, UCS, LAML, and TGCT. Integrated data underscored the critical involvement of NTMT1 in HNSC. Furthermore, the expression of NTMT1 was closely associated with tumor stage and immune infiltration in HNSC. Functionally, NTMT1 deficiency was demonstrated to significantly impede cell proliferation and cell-cycle progression in HNSC. Mechanistically, METTL3 was elucidated to mediate the epigenetic upregulation of NTMT1 in HNSC in an m6A-dependent manner, and the overexpression of METTL3 was shown to alleviate the inhibitory impact of downregulated NTMT1 on HNSC proliferation. In conclusion, our findings enhance our understanding of NTMT1's role across various cancer types and offer a rationale for clinically targeting NTMT1 as a therapeutic approach for HNSC.

Keywords:  METTL3; N6-methyladenosine; NTMT1; head and neck squamous cell carcinoma; pan-cancer

DOI:  https://doi.org/10.1002/jbt.23603
Environ Toxicol. 2023 Nov 29.

Methyltransferase-like 3-mediated m6A modification of miR-1908-5p contributes to nasopharyngeal carcinoma progression by targeting homeodomain-only protein homeobox.

Yuanhong Zhou, Wei Li.

   BACKGROUND: N6-methyladenosine (m6A) modification interacting microRNAs (miRNAs) have been confirmed to participate in nasopharyngeal carcinoma (NPC) progression. This research investigated miR-1908-5p's function and regulatory mechanism in the tumorigenesis of NPC via m6A modification and targeting a key gene.
METHODS: The levels of miR-1908-5p, homeodomain-only protein homeobox (HOPX), and methyltransferase-like 3 (METTL3) expressions were detected via RT-qPCR. The correlation between miR-1908-5p and the HOPX/METTL3 axis, as well as their regulatory mechanism, was investigated by dual luciferase reporter, western blotting, and MeRIP assays. Moreover, the bio-functions of miR-1908-5p, HOPX, and METTL3 in NPC were explored through CCK8, transwell, caspase-3 activity, and xenograft tumor assays.
RESULTS: RT-qPCR results indicated a miR-1908-5p upregulation in NPC. Knocking down miR-1908-5p diminished the NPC cell viability and migration in vitro. In vivo, downregulating miR-1908-5p repressed NPC cell tumor growth. Moreover, HOPX was specifically targeted by miR-1908-5p, and HOPX downregulation led to reversal of the anti-tumor impact of the miR-1908-5p inhibitor against NPC cell malignancy. Also, METTL3 could mediate the m6A modification of miR-1908-5p to regulate its influence on NPC cells.
CONCLUSION: This study demonstrated that the METTL3-mediated m6A modification of miR-1908-5p enhanced the tumorigenesis of NPC by targeting HOPX. These findings propose new insights for NPC diagnosis and therapy.

Keywords:  HOPX; METTL3; miR-1908-5p; nasopharyngeal carcinoma

DOI:  https://doi.org/10.1002/tox.24032
J Gene Med. 2023 Nov 27. e3636

Long non-coding RNA linc00659 promotes tumour progression by regulating FZD6/Wnt/β-catenin signalling pathway in colorectal cancer via m6A reader IGF2BP1.

Shufen Xu, Zichun Liu, Qian Luo, Lisha Chang, Jie Ding, Yanan Xiao, Yangyang Zhang, Guoren Zhou, Keming Wang.

   BACKGROUND: Abnormal N6-methyladenosine (m6A) modification has become a driving factor in tumour development and progression. The linc00659 is abnormally highly expressed in digestive tract tumours and promotes cancer progression, but there is little research on the mechanism of linc00659 and m6A.
METHODS: The expression of linc00659 in colorectal cancer (CRC) tissues and cells was assessed by a quantitative real-time PCR. The proliferative capacity of CRC cells was determined by colony formation, Cell Counting Kit-8 and 5-ethynyl-2 deoxyuridine assays, and the migratory capacity of CRC was determined by wound healing and transwell assays and tube formation. In vivo, a xenograft tumour model was used to detect the effect of linc00659 on tumour growth. The Wnt/β-catenin signalling pathway and related protein expression levels were measured by western blotting. The binding of linc00659 to insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) was assessed by RNA pull-down and an immunoprecipitation assay. The effect of IGF2BP1 on FZD6 was detected by an RNA stability assay.
RESULTS: The expression of linc00659 was abnormally elevated in CRC tissues and cells compared to normal colonic tissues and cells. We confirm that linc00659 promotes the growth of CRC cells both in vivo and in vitro. Mechanistically, linc00659 binds to IGF2BP1 and specifically enhances its activity to stabilize the target gene FZD6. Therefore, linc00659 and IGF2BP1 activate the Wnt/β-catenin signalling pathway, promoting cell proliferation in CRC.
CONCLUSIONS: Our results show that linc00659 and IGF2BP1 cooperate to promote the stability of the target FZD6 mRNA, thereby facilitating CRC progression, which may represent a potential diagnostic, prognostic and therapeutic target for CRC.

Keywords:  FZD6; IGF2BP1; Wnt/β-catenin pathway; colorectal cancer; linc00659

DOI:  https://doi.org/10.1002/jgm.3636
Cytokine. 2023 Nov 30. pii: S1043-4666(23)00266-1. [Epub ahead of print]173 156388

IGF2BP2 attenuates intestinal epithelial cell ferroptosis in colitis by stabilizing m6A-modified GPX4 mRNA.

Wei Liu, Hui Zeng.

   BACKGROUND: Ulcerative colitis (UC) is a chronic and uncontrolled inflammatory bowel disease. N6-methyladenine (m6A) is a reversible mRNA modification method. IGF2BP2 is an RNA-binding protein regulated by m6A methylation. However, understanding of m6A-related proteins in UC is limited. This study was to analyze the function and related mechanism of IGF2BP2 in UC.
METHODS: The UC models were established by dextran sulfate sodium (DSS) in NCM460 cells and mice. The expression of IGF2BP2 and GPX4 in UC were detected by qPCR and western blot. The effects of IGF2BP2 on inflammation, ferroptosis and colon injury were measured by gain- and loss-of-function experiments. This study conducted a clinical evaluation of mice using the Disease Activity Index score. The molecular mechanism of IGF2BP2 in ferroptosis were analyzed by m6A RNA methylation quantification kit, RNA immunoprecipitation-qPCR analysis, and RNA stability assay.
RESULTS: IGF2BP2 and GPX4 were under-expressed in DSS-treated UC. IGF2BP2 enhanced the stability of GPX4 mRNA modified by m6A. IGF2BP2 overexpression repressed the ROS, MDA, and iron levels but enhanced the GSH and GPX4 levels in DSS-triggered NCM460 cells, which were partially reversed by GPX4 silencing. In UC mice, IGF2BP2 high-expression ameliorated symptoms, Disease Activity Index score, pathological changes, inflammatory reaction, and ferroptosis, which were also partly neutralized by GPX4 inhibition.
CONCLUSIONS: IGF2BP2 augmented the GPX4 expression by the m6A modification to weaken UC progression via suppressing ferroptosis.

Keywords:  Ferroptosis; GPX4; IGF2BP2; M(6)A mRNA modification; Ulcerative colitis

DOI:  https://doi.org/10.1016/j.cyto.2023.156388
Mol Cell. 2023 Nov 24. pii: S1097-2765(23)00911-5. [Epub ahead of print]

m6A modification negatively regulates translation by switching mRNA from polysome to P-body via IGF2BP3.

Ting Shan, Feiyan Liu, Miaomiao Wen, Zonggui Chen, Shaopeng Li, Yafen Wang, Hong Cheng, Yu Zhou.

  In the cytoplasm, mRNAs are dynamically partitioned into translating and non-translating pools, but the mechanism for this regulation has largely remained elusive. Here, we report that m6A regulates mRNA partitioning between polysome and P-body where a pool of non-translating mRNAs resides. By quantifying the m6A level of polysomal and cytoplasmic mRNAs with m6A-LAIC-seq and m6A-LC-MS/MS in HeLa cells, we observed that polysome-associated mRNAs are hypo-m6A-methylated, whereas those enriched in P-body are hyper-m6A-methylated. Downregulation of the m6A writer METTL14 enhances translation by switching originally hyper-m6A-modified mRNAs from P-body to polysome. Conversely, by proteomic analysis, we identify a specific m6A reader IGF2BP3 enriched in P-body, and via knockdown and molecular tethering assays, we demonstrate that IGF2BP3 is both necessary and sufficient to switch target mRNAs from polysome to P-body. These findings suggest a model for the dynamic regulation of mRNA partitioning between the translating and non-translating pools in an m6A-dependent manner.

Keywords:  IGF2BP3; P-body; m(6)A modification; mRNA partitioning; polysome profiling; translation

DOI:  https://doi.org/10.1016/j.molcel.2023.10.040
Cancer Cell Int. 2023 Nov 27. 23(1): 298

Therapeutic effect and transcriptome-methylome characteristics of METTL3 inhibition in liver hepatocellular carcinoma.

Qingbin Liu, Jingjing Qi, Weiyang Li, Xinchen Tian, Jiaqi Zhang, Fen Liu, Xiulian Lu, Hengchang Zang, Chenqiao Liu, Changlin Ma, Yong Yu, Shulong Jiang.

  Methyltransferase-like 3 (METTL3) is the key subunit of methyltransferase complex responsible for catalyzing N6-methyladenosine (m6A) modification on mRNA, which is the most prevalent post-transcriptional modification in eukaryotes. In this study, we utilized online databases to analyze the association between METTL3 expression and various aspects of tumorigenesis, including gene methylation, immunity, and prognosis. Our investigation revealed that METTL3 serves as a prognostic marker and therapeutic target for liver hepatocellular carcinoma (LIHC). Through experimental studies, we observed frequent upregulation of METTL3 in LIHC tumor tissue and cells. Subsequent inhibition of METTL3 using a novel small molecule inhibitor, STM2457, significantly impeded tumor growth in LIHC cell lines, spheroids, and xenograft tumor model. Further, transcriptome and m6A sequencing of xenograft bodies unveiled that inhibition of METTL3-m6A altered genes enriched in SMAD and MAPK signaling pathways that are critical for tumorigenesis. These findings suggest that targeting METTL3 represents a promising therapeutic strategy for LIHC.

Keywords:  LIHC; MAPK; METTL3; SMAD; m6A

DOI:  https://doi.org/10.1186/s12935-023-03096-1