FAM50A drives breast cancer brain metastasis through interaction with C9ORF78 to enhance ʟ-asparagine production

IF 12.5 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Advances Pub Date : 2025-06-18 DOI:10.1126/sciadv.adt3075

Weilong Chen, Yuanyuan Qin, Libo Qiao, Xue Liu, Chenyun Gao, Tian-Ran Li, Yanrui Luo, Dongxue Li, Hong Yan, Linhong Han, Long Hai, Fang Nie, Hai-Bo Wu, Cong Chen, Yi-Fang Ping, Xiu-Wu Bian

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Abstract

Elevated levels of asparagine, catalyzed by asparagine synthetase (ASNS), have been identified as a prerequisite for lung metastasis in breast cancer. However, the roles and regulatory mechanisms of ASNS in breast cancer brain metastasis (BCBM) are not well understood. Our study revealed that the family with sequence similarity 50 member A (FAM50A) gene substantially modulates the brain metastatic potential of breast cancer by up-regulating ASNS and promoting asparagine biosynthesis. We demonstrated that FAM50A forms a complex with chromosome 9 open reading frame 78 (C9ORF78), specifically at the S121 residue, to enhance ASNS transcription. This interaction accelerates the rate of ASNS-mediated asparagine synthesis, which is essential in facilitating metastatic cascades to the brain. From a therapeutic perspective, both the genetic suppression of FAM50A and pharmacological inhibition of asparagine synthesis effectively counteract BCBM. Our results highlight the importance of the FAM50A-ASNS signaling pathway in BCBM therapy.

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FAM50A通过与C9ORF78相互作用促进_ -天冬酰胺的产生，从而驱动乳腺癌脑转移

由天冬酰胺合成酶（ASNS）催化的天冬酰胺水平升高已被确定为乳腺癌肺转移的先决条件。然而，ASNS在乳腺癌脑转移（BCBM）中的作用和调控机制尚不清楚。我们的研究发现，序列相似50成员A家族（FAM50A）基因通过上调ASNS和促进天冬酰胺的生物合成，实质性地调节乳腺癌的脑转移潜能。我们证明FAM50A与9号染色体开放阅读框78 （C9ORF78）形成复合体，特别是在S121残基处，以增强ASNS转录。这种相互作用加速了asns介导的天冬酰胺合成的速度，这在促进转移级联到大脑中是必不可少的。从治疗角度来看，FAM50A基因抑制和天冬酰胺合成的药理抑制都能有效对抗BCBM。我们的研究结果强调了FAM50A-ASNS信号通路在BCBM治疗中的重要性。

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来源期刊

Science Advances 综合性期刊-综合性期刊

CiteScore

21.40

自引率

1.50%

发文量

1937

审稿时长

29 weeks

期刊介绍： Science Advances, an open-access journal by AAAS, publishes impactful research in diverse scientific areas. It aims for fair, fast, and expert peer review, providing freely accessible research to readers. Led by distinguished scientists, the journal supports AAAS's mission by extending Science magazine's capacity to identify and promote significant advances. Evolving digital publishing technologies play a crucial role in advancing AAAS's global mission for science communication and benefitting humankind.