Notch-Driven Cholangiocarcinogenesis Involves the Hippo Pathway Effector TAZ via METTL3-m6A-YTHDF1

Area of Science:

• Oncology
• Molecular Biology
• Epigenetics

Background:

• Notch and TAZ are known oncogenes involved in cholangiocarcinogenesis (CCA).
• The precise interaction mechanisms between Notch and TAZ in CCA remain largely unknown.
• Understanding these interactions is critical for developing targeted therapies.

Purpose of the Study:

• To elucidate the functional interaction between Notch and TAZ in cholangiocarcinoma.
• To identify the molecular mechanisms underlying this crosstalk.
• To explore the therapeutic potential of targeting this pathway.

Main Methods:

• Cholangiocarcinoma was induced in mice using oncogenes (Notch1 intracellular domain [NICD]/AKT).
• CCA xenografts were established in SCID mice.
• Quantitative reverse transcription polymerase chain reaction, Western blotting, immunohistochemistry, and chromatin immunoprecipitation-quantitative polymerase chain reaction were employed.

Main Results:

• TAZ is essential for NICD-driven cholangiocarcinogenesis.
• Notch activation upregulates methyltransferase like-3 (METTL3), which modifies TAZ mRNA via N6-adenosine methylation.
• METTL3 enhances TAZ protein translation, mediated by the m6A reader YTHDF1, establishing a Notch-METTL3-TAZ signaling cascade.

Conclusions:

• A novel Notch-METTL3-TAZ signaling cascade is identified as critical for CCA development and progression.
• This study provides new insights into Notch-TAZ pathway cooperation in CCA.
• The findings suggest potential therapeutic strategies targeting this pathway for CCA treatment.