2. Academic Validation
  3. YTHDF3 Induces the Translation of m6A-Enriched Gene Transcripts to Promote Breast Cancer Brain Metastasis

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

  • Cancer Cell. 2020 Dec 14;38(6):857-871.e7. doi: 10.1016/j.ccell.2020.10.004.
Guoqiang Chang 1,  Lei Shi 2,  Youqiong Ye 3,  Hailing Shi 4,  Lixian Zeng 2,  Shweta Tiwary 2,  Jason T Huse 5,  Lei Huo 5,  Li Ma 2,  Yongjie Ma 6,  Sicong Zhang 2,  Jianwei Zhu 2,  Victoria Xie 7,  Peng Li 1,  Leng Han 3,  Chuan He 8,  Suyun Huang 9
Affiliations

Affiliations

  • 1 Department of Human and Molecular Genetics, Institute of Molecular Medicine, VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA 23298, USA.
  • 2 Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • 3 Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston McGroven Medical School, Houston, TX 77030, USA.
  • 4 Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637, USA; Howard Hughes Medical Institute, Chicago, IL, USA; Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637, USA.
  • 5 Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • 6 Department of Tumor Cell Biology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
  • 7 M.D. Program, Baylor College of Medicine, Houston, TX77030, USA.
  • 8 Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637, USA; Howard Hughes Medical Institute, Chicago, IL, USA; Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637, USA. Electronic address: [email protected].
  • 9 Department of Human and Molecular Genetics, Institute of Molecular Medicine, VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA 23298, USA; Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: [email protected].
PMID: 33125861 DOI: 10.1016/j.ccell.2020.10.004
Abstract

Brain metastasis is a major cause of Cancer mortality, but its molecular mechanisms are severely understudied. In addition, little is known regarding the role of m6A reader YTHDF3 in human diseases. Here, we show that YTHDF3 overexpression clinically correlates with brain metastases in breast Cancer patients. YTHDF3 promotes Cancer cell interactions with brain endothelial cells and astrocytes, blood-brain barrier extravasation, angiogenesis, and outgrow. Mechanistically, YTHDF3 enhances the translation of m6A-enriched transcripts for ST6GALNAC5, GJA1, and EGFR, all associated with brain metastasis. Furthermore, overexpression of YTHDF3 in brain metastases is attributed to increased gene copy number and the autoregulation of YTHDF3 cap-independent translation by binding to m6A residues within its own 5' UTR. Our work uncovers an essential role of YTHDF3 in controlling the interaction between Cancer cells and brain microenvironment, thereby inducing brain metastatic competence.

Keywords

YTHDF3; brain metastasis; epigenetic regulation; gene amplification; m(6)A RNA methylation.

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