Dataset Information

METTL3 promotes intrahepatic cholangiocarcinoma progression by regulating IFIT2 expression in an m⁶A-YTHDF2-dependent manner.

ABSTRACT: N6-methyladenosine (m⁶A) RNA methylation has recently been found involving in regulatory mechanism of the tumor progression. Our aim was to explore the biological function and clinical significance of the m⁶A methyltransferase METTL3 in intrahepatic cholangiocarcinoma (ICC). In this study, we revealed that METTL3 was upregulated and predicted poor prognosis of patients with ICC. Multivariate regression analysis demonstrated that METTL3 expression was an independent predictor for overall survival in patients with ICC. Moreover, METTL3 knockdown inhibited ICC progression, while METTL3 overexpression showed the opposite effect. METTL3 inhibitor STM2457 also showed anti-tumor effect in ICC. Mechanistically, METTL3 transcription was driven by H3K4me3 activation. Upregulation of METTL3 mediated m⁶A modification of IFIT2 mRNA and accelerated IFIT2 mRNA decay in a YTHDF2-dependent manner, which promoted the development of ICC and lead to poorer prognosis. In summary, our findings revealed that H3K4me3 activation-driven METTL3 transcription promotes ICC progression by YTHDF2-mediated IFIT2 mRNA degradation, suggesting that METTL3 may serve as a potential target for human ICC therapy.

SUBMITTER: Xu QC

PROVIDER: S-EPMC8913368 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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METTL3 promotes intrahepatic cholangiocarcinoma progression by regulating IFIT2 expression in an m6A-YTHDF2-dependent manner.

Xu Qiong-Cong QC Tien Yi-Chih YC Shi Yin-Hao YH Chen Siyun S Zhu Ying-Qin YQ Huang Xi-Tai XT Huang Chen-Song CS Zhao Wei W Yin Xiao-Yu XY

Oncogene 20220129 11

N6-methyladenosine (m6A) RNA methylation has recently been found involving in regulatory mechanism of the tumor progression. Our aim was to explore the biological function and clinical significance of the m6A methyltransferase METTL3 in intrahepatic cholangiocarcinoma (ICC). In this study, we revealed that METTL3 was upregulated and predicted poor prognosis of patients with ICC. Multivariate regression analysis demonstrated that METTL3 expression was an independent predicto ...[more]

PMID: 35094011

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Project description:BackgroundIntrahepatic cholangiocarcinoma (ICC) is an aggressive cancer with exceedingly poor prognosis, and chemoresistance is a huge challenge for treatment. N6-methyladenosine (m6 A) modification plays an important role in the progression and chemoresistance of cancers. We aimed to investigate the oncogenic function and therapeutic significance of the m6 A binding protein, YTH domain family 2 (YTHDF2), in ICC progression and cisplatin-based chemotherapy.MethodsSeveral independent data sets were used to assess the expression of YTHDF2 in ICC, particularly in chemoresistant ICC. Knockdown and overexpression were used to evaluate the effects of YTHDF2 on tumourigenesis and cisplatin response in ICC. Multi-omics sequencing was performed to identify target genes. RIP, dual luciferase reporter, RNA stability experiment and loss-of-function assays were conducted to study the mechanisms underlying the oncogenic function of YTHDF2. Furthermore, patient-derived xenograft (PDX) model was established to determine the effect of combination treatment of YTHDF2 siRNA and cisplatin in ICC.ResultsOur study showed that YTHDF2 was upregulated in ICC tissues, particularly in chemoresistant ICC tissues, and correlated with poor prognosis. Furthermore, silencing YTHDF2 led to inhibited proliferation, promoted apoptosis and G0/G1 cell cycle arrest. Its downregulation also enhanced DNA damage and sensitised ICC cells to cisplatin. YTHDF2 overexpression exerted the opposite results. Integration analysis using RNA-seq, MeRIP-seq and anti-YTHDF2 RIP-seq elucidated the role of YTHDF2 in tumourigenesis and cisplatin-desensitising function by promoting the degradation of cyclin-dependent kinase inhibitor 1B (CDKN1B) mRNA in an m6 A-dependent manner. Downregulation of CDKN1B increased the YTHDF2 silencing-induced influence on tumourigenesis and cisplatin response to ICC. In addition, the combination treatment of YTHDF2 siRNA and cisplatin significantly enhanced the anti-tumour effect of cisplatin in a chemoresistant ICC PDX model.ConclusionsYTHDF2 exhibits tumour oncogenic and cisplatin-desensitising properties, which may offer insight into the development of novel combination therapeutic strategies for ICC.

Project description:The present study aimed to explore the potential roles of the methyltransferase‑like 3 (METTL3)‑mediated methylation of RAS related (RRAS) mRNA in the tumorigenesis and development of bladder cancer (BCa). For this purpose, the relative expression levels of METTL3 in BCa specimens and cell lines were measured using reverse transcription‑quantitative PCR (RT‑qPCR) and western blot analysis. The association between the METTL3 expression level and the clinical characteristics of patients with BCa was analyzed using The Cancer Genome Atlas (TCGA) and Gene Expression Profiling Interactive Analysis databases. Cellular experiments were performed to confirm the effects of METTL3 on the proliferative, migratory and invasive capacities of BCa cells. RT‑qPCR, western blot analysis, methylated RNA immunoprecipitation (MeRIP)‑qPCR and dual‑luciferase report assays were utilized to verify the METTL3/RRAS/YTH N6‑methyladenosine (m6A) RNA binding protein 2 (YTHDF2) regulatory axis in BCa. The results revealed that METTL3 expression was markedly increased in BCa specimens and cell lines, and was associated with poor clinical characteristics of patients with BCa. In vitro and in vivo assays demonstrated that the silencing of METTL3 markedly suppressed the proliferative, migratory and invasive capacities of BCa cells. MeRIP‑PCR and dual‑luciferase report assays indicated that METTL3 could bind to the m6A sites of RRAS mRNA and suppress the transcriptional activity of RRAS. YTHDF2 could recognize the m6A sites of RRAS and mediate RRAS degradation. On the whole, the findings of the present study reveal the pivotal role of METTL3‑catalyzed m6A modification in BCa tumorigenesis and development. The change could facilitate BCa tumor growth and metastasis by suppressing RRAS expression in an m6A YTHDF2‑dependent manner. Targeting the METTL3/RRAS/YTHDF2 regulatory axis may thus prove to be a promising strategy for the diagnosis and therapy of BCa.

Dataset Information

METTL3 promotes intrahepatic cholangiocarcinoma progression by regulating IFIT2 expression in an m⁶A-YTHDF2-dependent manner.

Publications

METTL3 promotes intrahepatic cholangiocarcinoma progression by regulating IFIT2 expression in an m<sup>6</sup>A-YTHDF2-dependent manner.

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