An in vivo screen identifies NAT10 as a master regulator of brain metastasis
Emerging evidence has shown that epigenetic regulation plays a fundamental role in cancer metastasis, the major cause of cancer-related deaths. Here, we conducted an in vivo screen for vulnerabilities of brain metastasis and identified <i>N</i>-acetyltransferase 10 (NAT10) as a driver of brain metastasis. Knockdown of NAT10 restrains cancer cell proliferation and migration in vitro and tumor growth and brain metastasis in vivo. The poorly characterized RNA helicase domain of NAT10 is critical for cell growth in vitro, while both RNA helicase and NAT domains are essential for primary tumor growth and brain metastasis in vivo. Mechanically, NAT10 promotes the expression of 3-phosphoglycerate dehydrogenase (PHGDH) and phosphoserine aminotransferase 1 (PSAT1), two enzymes for serine biosynthesis implicated in brain metastasis. Silencing <i>PHGDH</i> or <i>PSAT1</i> in metastatic breast cancer cells inhibits their growth in the serine/glycine-limited condition, phenocopying the effects of NAT10 depletion. These findings establish NAT10 as a key regulator of brain metastasis and nominate NAT10 as a target for treating metastasis.
Authors
- Toma Tebaldi (ORCID: https://orcid.org/0000-0002-0625-1631)
- Emily Wingrove
- Hongying Shen (ORCID: https://orcid.org/0000-0002-2115-7037)
- Wenxue Li (ORCID: https://orcid.org/0000-0002-8902-0184)
- Peng Xu (ORCID: https://orcid.org/0000-0003-0822-700X)
- Mingzhu Yin (ORCID: https://orcid.org/0000-0002-6964-7131)
- Yansheng Liu (ORCID: https://orcid.org/0000-0002-2626-3912)
- Wesley L. Cai (ORCID: https://orcid.org/0000-0002-3871-5509)
- Ethan D. Krop (ORCID: https://orcid.org/0000-0002-4724-3865)
- Jocelyn Fang-Yi Chen (ORCID: https://orcid.org/0000-0001-7281-8686)
- Thomas F. Westbrook (ORCID: https://orcid.org/0009-0006-9711-5710)
- Don X. Nguyen (ORCID: https://orcid.org/0000-0003-0324-5604)
- Xiaojian Shi (ORCID: https://orcid.org/0000-0001-7456-2901)
- Stephanie Halene (ORCID: https://orcid.org/0000-0002-2737-9810)
- Qin Yan (ORCID: https://orcid.org/0000-0003-4077-453X)
- Yangyi Zhang (ORCID: https://orcid.org/0000-0002-5465-6334)
- Huacui Chen (ORCID: https://orcid.org/0000-0002-2768-4268)
- Amer Balabaki (ORCID: https://orcid.org/0000-0002-1509-886X)
- Jordan L. Meier (ORCID: https://orcid.org/0000-0002-0537-7101)
- Giulia Biancon (ORCID: https://orcid.org/0000-0003-0182-7766)
- Meiling Zhang (ORCID: https://orcid.org/0009-0004-9878-9763)
- Elianna Asare
Institutions
- National Institutes of Health (US)
- University of Trento (IT)
- Yale Cancer Center (US)
- Yale University (US)
- National Cancer Institute (US)
- Baylor Genetics (US)
Publication Details
- Journal
- Science Advances
- Published
- 2025-03-26
- DOI
- https://doi.org/10.1126/sciadv.ads6021
- Citations
- 4
- Primary Topic
- Epigenetics and DNA Methylation
- Type
- article
- Field-Weighted Citation Impact
- 3.22