Zheng Cuimiao, Niu Gang, Tan Hao, Huang Xi, Lu Jingyi, Mai Qiuwen, Yu Tiantian, Zhang Chunyu, Chen Siqi, Wei Mengxun, Pan Wenfeng, Guo Yu, Wang Jing, Xu Manman, Yao Shuzhong, Liu Junxiu, Li Jie, Pan Chaoyun
Department of Obstetrics and Gynecology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China.
Department of Biochemistry and Molecular Biology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China.
Nat Commun. 2025 Apr 3;16(1):3174. doi: 10.1038/s41467-025-58525-8.
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.
卵巢肿瘤细胞在腹水中实现不依赖锚定的存活是腹膜转移的起始关键步骤。卵巢肿瘤细胞如何实现不依赖锚定尚不清楚。在此，我们表明亚精胺/精胺N1-乙酰基转移酶1（SAT1）的非经典作用决定了不依赖锚定的细胞存活，并增强了卵巢癌的转移扩散。SAT1高表达的癌细胞在腹水肿瘤中很普遍，原发性肿瘤中SAT1的高表达与卵巢癌患者腹膜转移率增加有关。从机制上讲，SAT1以非经典方式使多个有丝分裂调节基因中的H3K27结构域乙酰化，提高其转录水平，并保护播散细胞免受异常有丝分裂和有丝分裂细胞死亡的影响。值得注意的是，SAT1对H3K27的乙酰化依赖于谷氨酰胺的还原羧化以在细胞核中提供乙酰辅酶A。用小分子抑制剂银杏内酯B抑制SAT1可减轻小鼠模型中的转移性肿瘤负担。我们得出结论，抑制SAT1是转移性卵巢癌一种有前景的治疗策略。
