Zhu Kaiyuan, Lv Qing, Lu Xiaoxia, Wang Yuchen, Dai Xiaofeng
Department of Thyroid and Breast Surgery, Affiliated Hospital of Jiangnan University, Wuxi, China.
Department of Oncology, Affiliated Hospital of Yangzhou University, Yangzhou, 225000, China.
Free Radic Biol Med. 2025 Jan;226:364-373. doi: 10.1016/j.freeradbiomed.2024.11.028. Epub 2024 Nov 23.
Breast cancer is the most common cancer diagnosed and the second leading cause of death of cancer among women in the world, due to inappropriate diagnosis and choice of therapeutic approach. The molecular profiles of breast cancers may switch among subtypes during treatments, leading to a phenotype such as triple negative breast cancers (TNBCs) that is more difficult to treat. Cold atmospheric plasma (CAP) has been demonstrated by many studies on its efficacy in arresting the malignancies of multiple cancer types including TNBCs that lack surface receptor expression and are thus the most difficult to treat among breast cancers. By analyzing the genetic testing reports of a breast cancer clinical case misdiagnosed with BRCA1 mutation, we characterized the importance of KAT6A in driving disease progression of this patient. Through exploring genes differentially regulated under physical interactions between KAT6A and SMAD3, we proposed the KAT6A/SMAD3/IL6/CD163 molecular axis capable of driving macrophage M2 polarization in the immune microenvironment of breast cancers. Through examining the expression landscapes of KAT6A at both transcriptional and translational levels, we proposed a possible role of KAT6A acetylation in reducing its ability in acetylating SMAD3 and subsequent oncogenic roles. Through analyzing the whole transcriptome and acetylome of TNBC cells in response to CAP treatment, we predicted the efficacy of CAP in resolving TNBCs via increasing KAT6A acetylation, which were validated both in vitro and in vivo. Our study, for the first time, presented the role of CAP in re-polarizing macrophages from the M2 to M1 state in the microenvironment of breast cancers via elevating KAT6A acetylation, and warranted careful interpretation of patients' genetic testing reports by clinicians for the sake of minimizing mortalities due to inappropriate choice of therapeutic modalities.
由于诊断不当和治疗方法选择不当，乳腺癌是世界上女性中诊断出的最常见癌症，也是癌症死亡的第二大主要原因。乳腺癌的分子特征在治疗过程中可能会在不同亚型之间转换，导致出现如三阴性乳腺癌（TNBC）这样更难治疗的表型。许多研究已证明冷大气等离子体（CAP）在抑制多种癌症类型的恶性肿瘤方面具有功效，包括缺乏表面受体表达、因而在乳腺癌中最难治疗的TNBC。通过分析一例被误诊为BRCA1突变的乳腺癌临床病例的基因检测报告，我们确定了KAT6A在推动该患者疾病进展中的重要性。通过探索在KAT6A与SMAD3物理相互作用下差异调节的基因，我们提出了KAT6A/SMAD3/IL6/CD163分子轴，其能够在乳腺癌免疫微环境中驱动巨噬细胞M2极化。通过在转录和翻译水平检查KAT6A的表达情况，我们提出KAT6A乙酰化可能在降低其乙酰化SMAD3的能力及后续致癌作用方面发挥作用。通过分析TNBC细胞响应CAP治疗的全转录组和乙酰化组，我们预测CAP通过增加KAT6A乙酰化来解决TNBC的功效，这在体外和体内均得到了验证。我们的研究首次展示了CAP在乳腺癌微环境中通过提高KAT6A乙酰化使巨噬细胞从M2状态重新极化到M1状态的作用，并促使临床医生仔细解读患者的基因检测报告，以尽量减少因治疗方式选择不当导致的死亡率。
