YTHDF3 Induces the Translation of m⁶A-Enriched Gene Transcripts to Promote Breast Cancer Brain Metastasis

Area of Science:

• Molecular Oncology
• Cancer Metastasis
• Epigenetics

Background:

• Brain metastasis is a leading cause of cancer mortality with poorly understood molecular drivers.
• The role of the N6-methyladenosine (m6A) reader protein YTHDF3 in human diseases, particularly cancer metastasis, is largely unknown.

Purpose of the Study:

• To investigate the role of YTHDF3 in breast cancer brain metastasis.
• To elucidate the molecular mechanisms by which YTHDF3 promotes brain metastatic competence.

Main Methods:

• Clinical correlation analysis of YTHDF3 expression in breast cancer patients with brain metastases.
• In vitro and in vivo assays to assess YTHDF3's effects on cancer cell interactions with brain microenvironment components (endothelial cells, astrocytes).
• Analysis of YTHDF3-mediated translation of specific m6A-enriched transcripts (ST6GALNAC5, GJA1, EGFR).
• Investigation of mechanisms driving YTHDF3 overexpression, including gene copy number and autoregulation.

Main Results:

• YTHDF3 overexpression is clinically associated with brain metastases in breast cancer.
• YTHDF3 promotes critical steps in brain metastasis: cancer cell adhesion, blood-brain barrier extravasation, angiogenesis, and tumor outgrow.
• YTHDF3 enhances the translation of m6A-modified transcripts encoding ST6GALNAC5, GJA1, and EGFR, which are implicated in brain metastasis.
• YTHDF3 overexpression in brain metastases results from increased gene copy number and autoregulation via m6A-dependent cap-independent translation.

Conclusions:

• YTHDF3 plays a critical role in mediating breast cancer brain metastasis.
• YTHDF3 controls cancer cell interactions with the brain microenvironment, facilitating metastatic colonization.
• Targeting YTHDF3 may offer a novel therapeutic strategy to prevent or treat brain metastases.