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

被引：402

作者：

Chang, Guoqiang ^{[1
]}

Shi, Lei ^{[2
]}

Ye, Youqiong ^{[4
]}

Shi, Hailing ^{[7
,8
,9
,10
]}

Zeng, Lixian ^{[2
]}

Tiwary, Shweta ^{[2
]}

Huse, Jason T. ^{[3
]}

Huo, Lei ^{[3
]}

Ma, Li ^{[2
]}

Ma, Yongjie ^{[5
]}

Zhang, Sicong ^{[2
]}

Zhu, Jianwei ^{[2
]}

Xie, Victoria ^{[6
]}

Li, Peng ^{[1
]}

Han, Leng ^{[4
]}

He, Chuan ^{[7
,8
,9
,10
]}

Huang, Suyun ^{[1
,2
]}

机构：

[1] Virginia Commonwealth Univ, VCU Massey Canc Ctr, Dept Human & Mol Genet, Inst Mol Med,Sch Med, Richmond, VA 23298 USA

[2] Univ Texas MD Anderson Canc Ctr, Dept Neurosurg, Houston, TX 77030 USA

[3] Univ Texas Hlth Sci Ctr Houston, Dept Biochem & Mol Biol, McGroven Med Sch, Dept Pathol, Houston, TX 77030 USA

[4] Univ Texas Hlth Sci Ctr Houston, Dept Biochem & Mol Biol, McGroven Med Sch, Houston, TX 77030 USA

[5] Tianjin Med Univ Canc Inst & Hosp, Dept Tumor Cell Biol, Tianjin, Peoples R China

[6] Baylor Coll Med, MD Program, Houston, TX 77030 USA

[7] Univ Chicago, Dept Chem, Chicago, IL 60637 USA

[8] Univ Chicago, Inst Biophys Dynam, Chicago, IL 60637 USA

[9] Howard Hughes Med Inst, Chicago, IL USA

[10] Univ Chicago, Dept Biochem & Mol Biol, Chicago, IL 60637 USA

来源：

CANCER CELL | 2020年 / 38卷 / 06期

关键词：

RNA MODIFICATIONS; EXPRESSION; CELLS; MICROENVIRONMENT; EPIDEMIOLOGY; ACTIVATION; LEUKEMIA; PATHWAY; STAT3;

D O I：

10.1016/j.ccell.2020.10.004

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

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 m(6)A 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 m(6)A-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 tom m(6)A residues within its own 50 UTR. Our work uncovers an essential role of YTHDF3 in controlling the interaction between cancer cells and brain microenvironment, thereby inducing brain metastatic competence.

引用

页码：857 / +

页数：22

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