A noncanonical role of SAT1 enables anchorage independence and peritoneal metastasis in ovarian cancer
Anchorage-independent survival of ovarian tumor cells in ascites is the initial and critical step for peritoneal metastasis. How ovarian tumor cells achieve anchorage independence remains unclear. Here we show that a noncanonical role of spermidine/spermine N1-acetyltransferase 1 (SAT1) dictates anchorage-independent cell survival and potentiates metastatic dissemination in ovarian cancer. SAT1-high cancer cells are prevalent in ascitic tumors, and high SAT1 expression in primary tumors is linked to increased peritoneal metastasis rates in ovarian cancer patients. Mechanistically, SAT1 noncanonically acetylates H3K27 domains in multiple mitosis-regulating genes, increasing their transcriptional levels and protecting disseminating cells from aberrant mitosis and mitotic cell death. Notably, the acetylation of H3K27 by SAT1 depends on the reductive carboxylation of glutamine to supply acetyl-CoA in the nucleus. SAT1 inhibition with the small-molecule inhibitor ginkgolide B attenuates the metastatic tumor burden in mouse models. We conclude that SAT1 inhibition is a promising therapeutic strategy for metastatic ovarian cancer.
Authors
- Shuzhong Yao (ORCID: https://orcid.org/0000-0002-5145-5705)
- Manman Xu (ORCID: https://orcid.org/0000-0002-1297-9477)
- Tiantian Yu (ORCID: https://orcid.org/0009-0005-1848-0748)
- Hao Tan (ORCID: https://orcid.org/0000-0001-8808-5448)
- Yu Guo (ORCID: https://orcid.org/0000-0002-8886-0106)
- Chaoyun Pan (ORCID: https://orcid.org/0000-0002-4255-9318)
- Mengxun Wei
- Xi Huang (ORCID: https://orcid.org/0000-0002-0896-6980)
- Jingyi Lu (ORCID: https://orcid.org/0000-0003-1105-4189)
- Cuimiao Zheng (ORCID: https://orcid.org/0000-0002-1177-0575)
- Siqi Chen (ORCID: https://orcid.org/0009-0003-7260-3070)
- Wenfeng Pan (ORCID: https://orcid.org/0000-0001-7719-6070)
- Junxiu Liu (ORCID: https://orcid.org/0000-0002-7892-6343)
- Jing Wang (ORCID: https://orcid.org/0000-0002-7501-8702)
- Jie Li (ORCID: https://orcid.org/0000-0003-1232-3248)
- Chunyu Zhang (ORCID: https://orcid.org/0000-0002-8112-0201)
- Gang Niu (ORCID: https://orcid.org/0000-0002-1694-4239)
- Qiuwen Mai (ORCID: https://orcid.org/0000-0002-9039-9435)
Institutions
- Sun Yat-sen University (CN)
- National Clinical Research Center for Digestive Diseases (CN)
- Guangdong Province Stomatological Hospital (CN)
- The First Affiliated Hospital, Sun Yat-sen University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-04-03
- DOI
- https://doi.org/10.1038/s41467-025-58525-8
- Citations
- 8
- Primary Topic
- PARP inhibition in cancer therapy
- Type
- article
- Field-Weighted Citation Impact
- 8.36
Funders
- National Natural Science Foundation of China