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.
Gallbladder cancer (GBC) is the most
aggressive malignancy of the
biliary tract cancer, and there is a lack of effective treatment.
Here, we developed a nanoparticle platform (8P4 NP) that can deliver
THZ1, a cyclin-dependent kinase 7 (CDK7) inhibitor, to treat GBC.
Analysis of datasets demonstrated that CDK7 was positively correlated
with poor prognosis. CDK7 inhibition suppressed cell proliferation,
induced apoptosis, and caused cell cycle block in GBC cells. THZ1
downregulated CDK7-mediated phosphorylation of RNA polymerase II (RNAPII),
resulting in a significant downregulation of transcriptional programs,
with a preferential repression of oncogenic transcription factors.
To improve the tumor targeting efficiency of THZ1, 8P4 NPs were prepared
and assembled with THZ1 to form THZ1@8P4 NPs. Compared with free THZ1,
THZ1@8P4 NPs showed more advantages in prolonging blood circulation,
escaping from lysosomes and increasing cellular uptake. Importantly,
THZ1@8P4 NPs demonstrated a more significant inhibition effect on
GBC cells than free THZ1 in vitro. In addition, THZ1@8P4
NPs could efficiently deliver THZ1 to tumor sites in a patient-derived
xenograft model of early recurrence, leading to tumor regression and
transcriptional inhibition with minimal toxicity. In summary, we conclude
that THZ1@8P4 NPs provide a potent therapeutic strategy that targets
CDK7-mediated transcriptional addiction in GBC.
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