METTL3 promotes pancreatic cancer proliferation and stemness by increasing stability of ID2 mRNA in a m6A-dependent manner

Chen, Jiaoshun; Zhang, Haoxiang; Xiu, Chaoyang; Gao, Chenggang; Wu, Shihong; Bai, Jianwei; Shen, Qiang; Yin, Tao

doi:10.1016/j.canlet.2023.216222

Cited by 10 publications

(7 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Interestingly, we wondered why the decrease in mRNA m 5 C modification was correlated with a decrease in gene expression. Recent studies have shown that modifications to transcripts can affect their stability [ 33 – 36 ]. Specifically, certain RNA-binding proteins (RBPs) can recognize and bind to these modification sites, thereby affecting their translation.…”

Section: Resultsmentioning

confidence: 99%

NSUN2/YBX1 promotes the progression of breast cancer by enhancing HGH1 mRNA stability through m5C methylation

Zhang,

An,

et al. 2024

Breast Cancer Res

View full text Add to dashboard Cite

Background RNA m5C methylation has been extensively implicated in the occurrence and development of tumors. As the main methyltransferase, NSUN2 plays a crucial regulatory role across diverse tumor types. However, the precise impact of NSUN2-mediated m5C modification on breast cancer (BC) remains unclear. Our study aims to elucidate the molecular mechanism underlying how NSUN2 regulates the target gene HGH1 (also known as FAM203) through m5C modification, thereby promoting BC progression. Additionally, this study targets at preliminarily clarifying the biological roles of NSUN2 and HGH1 in BC. Methods Tumor and adjacent tissues from 5 BC patients were collected, and the m5C modification target HGH1 in BC was screened through RNA sequencing (RNA-seq) and single-base resolution m5C methylation sequencing (RNA-BisSeq). Methylation RNA immunoprecipitation-qPCR (MeRIP-qPCR) and RNA-binding protein immunoprecipitation-qPCR (RIP-qPCR) confirmed that the methylation molecules NSUN2 and YBX1 specifically recognized and bound to HGH1 through m5C modification. In addition, proteomics, co-immunoprecipitation (co-IP), and Ribosome sequencing (Ribo-Seq) were used to explore the biological role of HGH1 in BC. Results As the main m5C methylation molecule, NSUN2 is abnormally overexpressed in BC and increases the overall level of RNA m5C. Knocking down NSUN2 can inhibit BC progression in vitro or in vivo. Combined RNA-seq and RNA-BisSeq analysis identified HGH1 as a potential target of abnormal m5C modifications. We clarified the mechanism by which NSUN2 regulates HGH1 expression through m5C modification, a process that involves interactions with the YBX1 protein, which collectively impacts mRNA stability and protein synthesis. Furthermore, this study is the first to reveal the binding interaction between HGH1 and the translation elongation factor EEF2, providing a comprehensive understanding of its ability to regulate transcript translation efficiency and protein synthesis in BC cells. Conclusions This study preliminarily clarifies the regulatory role of the NSUN2-YBX1-m5C-HGH1 axis from post-transcriptional modification to protein translation, revealing the key role of abnormal RNA m5C modification in BC and suggesting that HGH1 may be a new epigenetic biomarker and potential therapeutic target for BC.

show abstract

Section: Resultsmentioning

confidence: 99%

NSUN2/YBX1 promotes the progression of breast cancer by enhancing HGH1 mRNA stability through m5C methylation

Zhang,

An,

et al. 2024

Breast Cancer Res

View full text Add to dashboard Cite

show abstract

“… 21 Also, METTL3 promoted pancreatic cancer cell proliferation and stemness by increasing ID2 mRNA stability through m6A modification. 22 A recent study revealed that METTL3 had increased expression in NSCLC, which accelerated NSCLC cell growth and metastasis via the targeting inhibition of FDX1. 23 Moreover, METTL3 had been shown to serve as an oncogene in NSCLC via mediating the m6A modification of antiapoptosis marker Bcl‐2 mRNA.…”

Section: Discussionmentioning

confidence: 99%

METTL3‐mediated the m6A modification of SF3B4 facilitates the development of non‐small cell lung cancer by enhancing LSM4 expression

He,

Gu,

Wei

et al. 2024

Thoracic Cancer

View full text Add to dashboard Cite

BackgroundSplicing factor B subunit 4 (SF3B4) has been confirmed to participate in the progression of many cancers and is considered to be a potential target for non‐small cell lung cancer (NSCLC). Thus, the role and molecular mechanism of SF3B4 in NSCLC progression deserves further study.MethodsQuantitative real‐time PCR and western blot were employed to detect the mRNA and protein levels of SF3B4, Sm‐like protein 4 (LSM4) and methyltransferase‐like 3 (METTL3). Cell proliferation, apoptosis, invasion, migration and stemness were tested by cell counting kit‐8, colony formation, flow cytometry, transwell, wound healing, and sphere formation assays. The interaction between SF3B4 and METTL3 or LSM4 was confirmed by MeRIP, RIP and Co‐IP assays. Mice xenograft models were constructed to assess the effects of METTL3 and SF3B4 on NSCLC tumorigenesis.ResultsSF3B4 had high expression in NSCLC tissues and was associated with the shorter overall survival of NSCLC patients. Knockdown of SF3B4 suppressed NSCLC cell proliferation, invasion, migration and stemness, while inducing apoptosis. METTL3 promoted SF3B4 mRNA stability by m6A modification, and its knockdown inhibited NSCLC cell growth, metastasis and stemness by downregulating SF3B4. SF3B4 could interact with LSM4, and sh‐SF3B4‐mediated the inhibition on NSCLC cell functions could be reversed by LSM4 overexpression. In addition, reduced METTL3 expression restrained NSCLC tumor growth, and this effect was reversed by SF3B4 overexpression.ConclusionMETTL3‐stablized SF3B4 promoted NSCLC cell growth, metastasis and stemness via positively regulating LSM4.

show abstract

“…Previous studies have shown that RNA N6‐methyladenosine (m6A) methyltransferase METTL3 promotes the development of intestinal cancer and other cancers as a carcinogenic factor, [ 18,30 ] but its upstream mechanism remains unclear. In this study, we found that NSUN6 regulates the expression of METLL3 and its m5C modification level.…”

Section: Discussionmentioning

confidence: 99%

NSUN6 mediates 5‐methylcytosine modification of METTL3 and promotes colon adenocarcinoma progression

Cui,

Lv,

Zhang

2024

J Biochem & Molecular Tox

View full text Add to dashboard Cite

Colon adenocarcinoma (COAD) is a common and fatal malignant tumor of digestive system with complex etiology. 5‐Methylcytosine (m5C) modification of RNA by the NSUN gene family (NSUN1‐NSUN7) and DNMT2 reshape cell biology and regulate tumor development. However, the expression profile, prognostic significance and function of these m5C modifiers in COAD remain largely unclear. By mining multiple integrated tumor databases, we found that NSUN1, NSUN2, NSUN5, and NSUN6 were overexpressed in COAD tumor samples relative to normal samples. Clinically, high expression of NSUN6 was significantly associated with shorter survival (including both disease‐free survival and overall survival) in COAD patients. NSUN6 was further confirmed to be upregulated at both tissue and cellular levels of COAD, suggesting that NSUN6 plays a critical role in disease progression. Through comprehensive gene enrichment analysis and cell‐based functional validation, it was revealed that NSUN6 promoted the cell cycle progression and cell proliferation of COAD. Mechanistically, NSUN6 upregulates the expression of oncogenic METTL3 and catalyzes its m5C modification in COAD cells. Overexpression of METTL3 significantly relieved the cell cycle inhibition of COAD caused by NSUN6 deficiency. Furthermore, NSUN6 was negatively associated with the abundance of infiltrating immune cells in COAD tumors, such as activated B cells, natural killer cells, effector memory CD8 T cells, and regulatory T cells. Importantly, pan‐cancer analysis further uncovered that NSUN6 was dysregulated and heterogeneous in various tumors. Thus our findings extend the role of m5C transferase in COAD and suggest that NSUN6 is a potential biomarker and target for this malignancy.

show abstract

METTL3 promotes pancreatic cancer proliferation and stemness by increasing stability of ID2 mRNA in a m6A-dependent manner

Cited by 10 publications

References 34 publications

NSUN2/YBX1 promotes the progression of breast cancer by enhancing HGH1 mRNA stability through m5C methylation

NSUN2/YBX1 promotes the progression of breast cancer by enhancing HGH1 mRNA stability through m5C methylation

METTL3‐mediated the m6A modification of SF3B4 facilitates the development of non‐small cell lung cancer by enhancing LSM4 expression

NSUN6 mediates 5‐methylcytosine modification of METTL3 and promotes colon adenocarcinoma progression

Contact Info

Product

Resources

About