Breast cancer (BC) is the most common malignancy in women with unfavorite prognosis. Tanshinone IIA (Tan IIA) inhibits BC progression, however, the underlying mechanism remains largely undefined. The cytotoxicity of Tan IIA was assessed by CCK-8 and LDH assays. Ferroptosis was monitored by the level of MDA, Fe, lipid ROS and GSH. IHC and western blot were employed to detect the localization and expression of SLC7A11, PIAS4, KDM1A and other key molecules. The SUMOylation of SLC7A11 was detected by Ni-beads pull-down assay and Co-IP. Luciferase and ChIP assays were employed to detect the direct association between KDM1A and PIAS4 promoter. The proliferative and metastatic properties of BC cells were assessed by colony formation, CCK-8 and Transwell assays, respectively. The findings were verified in xenograft and lung metastasis models. Tan IIA promoted ferroptosis by suppressing SLC7A11 in BC cells. Silencing of PIAS4 or KDM1A inhibited cell growth and metastasis in BC. Mechanistically, PIAS4 facilitated the SUMOylation of SLC7A11 via direct binding to SLC7A11, and KDM1A acted as a transcriptional activator of PIAS4. Functional studies further revealed that Tan IIA decreased KDM1A expression, thus suppressing PIAS4 expression transcriptionally. The inhibition of PIAS4-dependent SUMOylation of SLC7A11 further induced ferroptosis, thereby inhibiting proliferation and metastasis in BC. Tan IIA promoted ferroptosis and inhibited tumor growth and metastasis via suppressing KDM1A/PIAS4/SLC7A11 axis.

中文翻译：

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丹参酮 IIA 通过 KDM1A 调节 PIAS4 介导的 SLC7A11 SUMO 化，从而破坏 SLC7A11 的稳定性，并促进乳腺癌铁死亡

乳腺癌（BC）是女性最常见的恶性肿瘤，预后不良。丹参酮 IIA (Tan IIA) 可抑制 BC 进展，但其潜在机制在很大程度上仍不清楚。通过 CCK-8 和 LDH 测定评估 Tan IIA 的细胞毒性。通过 MDA、Fe、脂质 ROS 和 GSH 的水平监测铁死亡。采用IHC和western blot检测SLC7A11、PIAS4、KDM1A等关键分子的定位和表达。通过 Ni-beads Pull-down 测定和 Co-IP 检测 SLC7A11 的 SUMOylation。采用荧光素酶和 ChIP 测定来检测 KDM1A 和 PIAS4 启动子之间的直接关联。分别通过集落形成、CCK-8 和 Transwell 测定评估 BC 细胞的增殖和转移特性。这些发现在异种移植和肺转移模型中得到了验证。 Tan IIA 通过抑制 BC 细胞中的 SLC7A11 促进铁死亡。 PIAS4 或 KDM1A 的沉默抑制了 BC 中的细胞生长和转移。从机制上讲，PIAS4 通过直接结合 SLC7A11 促进 SLC7A11 的 SUMO 化，而 KDM1A 充当 PIAS4 的转录激活剂。功能研究进一步表明 Tan IIA 降低 KDM1A 表达，从而抑制 PIAS4 转录表达。抑制 SLC7A11 的 PIAS4 依赖性 SUMO 化进一步诱导铁死亡，从而抑制 BC 的增殖和转移。 Tan IIA 通过抑制 KDM1A/PIAS4/SLC7A11 轴促进铁死亡并抑制肿瘤生长和转移。