A noncanonical role of SAT1 enables anchorage independence and peritoneal metastasis in ovarian cancer

Cuimiao Zheng, Gang Niu, Hao Tan, Xi Huang, Jingyi Lu, Qiuwen Mai, Tiantian Yu, Chunyu Zhang, Siqi Chen, Mengxun Wei, Wenfeng Pan, Yu Guo, Jing Wang, Manman Xu, Shuzhong Yao, Junxiu Liu (), Jie Li () and Chaoyun Pan ()
Additional contact information
Cuimiao Zheng: Sun Yat-sen University
Gang Niu: Sun Yat-sen University
Hao Tan: Sun Yat-sen University
Xi Huang: Sun Yat-sen University
Jingyi Lu: Sun Yat-sen University
Qiuwen Mai: Sun Yat-sen University
Tiantian Yu: Guangzhou
Chunyu Zhang: Sun Yat-sen University
Siqi Chen: Sun Yat-sen University
Mengxun Wei: Sun Yat-sen University
Wenfeng Pan: Sun Yat-sen University
Yu Guo: Sun Yat-sen University
Jing Wang: Sun Yat-sen University
Manman Xu: Sun Yat-sen University
Shuzhong Yao: Sun Yat-sen University
Junxiu Liu: Sun Yat-sen University
Jie Li: Sun Yat-sen University
Chaoyun Pan: Sun Yat-sen University

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-58525-8

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