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N6-methyladenosine modification of B7-H3 mRNA promotes the development and progression of colorectal cancer.

ABSTRACT: B7-H3 is a common oncogene found in various cancer types. However, the molecular mechanisms underlying abnormal B7-H3 expression and colorectal cancer (CRC) progression need to be extensively explored. B7-H3 was upregulated in human CRC tissues and its abnormal expression was correlated with a poor prognosis in CRC patients. Notably, gain- and loss-of-function experiments revealed that B7-H3 knockdown substantially inhibited cell proliferation, migration, and invasion in vitro, whereas exogenous B7-H3 expression yielded contrasting results. In addition, silencing of B7-H3 inhibited tumor growth in a xenograft mouse model. Mechanistically, our study demonstrated that the N6-methyladenosine (m6A) binding protein YTHDF1 augmented B7-H3 expression in an m6A-dependent manner. Furthermore, rescue experiments demonstrated that reintroduction of B7-H3 considerably abolished the inhibitory effects on cell proliferation and invasion induced by silencing YTHDF1. Our results suggest that the YTHDF1-m6A-B7-H3 axis is crucial for CRC development and progression and may represent a potential therapeutic target for CRC treatment.

SUBMITTER: Chen R

PROVIDER: S-EPMC10839442 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

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N6-methyladenosine modification of B7-H3 mRNA promotes the development and progression of colorectal cancer.

Chen Rui R Su Fei F Zhang Tao T Wu Dongjin D Yang Jingru J Guan Quanlin Q Chai Chen C

iScience 20240118 2

B7-H3 is a common oncogene found in various cancer types. However, the molecular mechanisms underlying abnormal B7-H3 expression and colorectal cancer (CRC) progression need to be extensively explored. B7-H3 was upregulated in human CRC tissues and its abnormal expression was correlated with a poor prognosis in CRC patients. Notably, gain- and loss-of-function experiments revealed that B7-H3 knockdown substantially inhibited cell proliferation, migration, and invasion <i>in vitro</i>, whereas ex ...[more]

PMID: 38318386

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Project description:BackgroundColorectal cancer (CRC) is one of the leading causes of tumor-related death worldwide, and its main cause of death is distant metastasis. Methyltransferase-like 14(METTL14), a major RNA N6-adenosine methyltransferase, is involved in tumor progression via regulating RNA function. The goal of the study is to uncover the biological function and molecular mechanism of METTL14 in CRC.MethodsQuantitative real-time PCR (qRT-PCR), western blot and immunohistochemical (IHC) assays were employed to detect METTL14 and SOX4 in CRC cell lines and tissues. The biological functions of METTL14 were demonstrated using in vitro and in vivo experiments. Chromatin immunoprecipitation (ChIP), Transcrptomic RNA sequencing (RNA-Seq), m6A-RNA immunoprecipitation sequencing (MeRIP-Seq), RNA immunoprecipitation and luciferase reporter assays were used to explore the mechanism of METTL14 action.ResultsMETTL14 expression was significantly downregulated in CRC and decreased METTL14 was associated with poor overall survival (OS). Both the univariate and multivariate Cox regression analysis indicated that METTL14 was an independent prognostic factor in CRC. Moreover, lysine-specific histone demethylase 5C(KDM5C)-mediated demethylation of histone H3 lysine 4 tri-methylation(H3K4me3) in the promoter of METTL14 inhibited METTL14 transcription. Functionally, we verified that METTL14 inhibited CRC cells migration, invasion and metastasis through in vitro and in vivo assays, respectively. Furthermore, we identified SRY-related high-mobility-group box 4(SOX4) as a target of METTL14-mediated m6A modification. Knockdown of METTL14 markedly abolished SOX4 mRNA m6A modification and elevated SOX4 mRNA expression. We also revealed that METTL14-mediated SOX4 mRNA degradation relied on the YTHDF2-dependent pathway. Lastly, we demonstrated that METTL14 might inhibit CRC malignant process partly through SOX4-mediated EMT process and PI3K/Akt signals.ConclusionsDecreased METTL14 facilitates tumor metastasis in CRC, suggesting that METTL14 might be a potential prognostic biomarker and effective therapeutic target for CRC.

Project description:BackgroundN6-methyladenosine (m6A) is associated with mammalian mRNA biogenesis, decay, translation and metabolism, and also contributes greatly to gastrointestinal tumor formation and development. Therefore, the specific mechanisms and signaling pathways mediated by methyltransferase-like 3 (METTL3), which catalyzes the formation of m6A chemical labeling in stomach adenocarcinoma (STAD), are still worth exploring.MethodsQuantitative real-time PCR (qRT-PCR) was constructed to detect the expression of METTL3 in gastric cancer cell lines and patient tissues. The biological function of METTL3 was investigated in vitro/in vivo by Cell Counting Kit-8, colony formation assay, Transwell assay and nude mouse tumorigenesis assay. Based on the LinkedOmics database, the genes co-expressed with METTL3 in the TCGA STAD cohort were analyzed to clarify the downstream targets of METTL3. Methylated RNA immunoprecipitation-qPCR (MeRIP-qPCR) and RNA stability analysis were employed to explore the mechanism of METTL3 in gastric cancer progression.ResultsWe analyzed TCGA data and found that METTL3 was frequently elevated in STAD, and demonstrated that METTL3 was present at high levels in clinical STAD tissues and cells. High METTL3 expression was more likely to have advanced TNM tumors and distant metastasis. On the other hand, METTL3 silencing effectively impeded the higher oncogenic capacity of AGS and HGC27 cells in vivo and in vitro, as reflected by slowed cell growth and diminished migration and invasion capacities. Continued mining of the TCGA dataset identified the co-expression of angiopoietin-like 3 (ANGPTL3) and METTL3 in STAD. Lower level of ANGPTL3 was related to increased level of METTL3 in STAD samples and shorter survival times in STAD patients. ANGPTL3 enrichment limited the growth and metastasis of STAD cells. Besides, ANGPTL3 mRNA levels could be decreased by METTL3-dominated m6A modifications, a result derived from a combination of MeRIP-qPCR and RNA half-life experiments. Importantly, the inhibitory effect of METTL3 silencing on cancer could be reversed to some extent by ANGPTL3 inhibition.ConclusionsOverall, our findings suggested that METTL3 functioned an oncogenic role in STAD by reducing ANGPTL3 expression in an m6A-dependent manner. The discovery of the METTL3-ANGPTL3 axis and its effect on STAD tumor growth will contribute to further studies on the mechanisms of gastric adenocarcinoma development.

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Dataset Information

N6-methyladenosine modification of B7-H3 mRNA promotes the development and progression of colorectal cancer.

Publications

N6-methyladenosine modification of B7-H3 mRNA promotes the development and progression of colorectal cancer.

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