昼夜节律振荡失调是各种实体瘤的显着特征。因此，阐明维持生物钟的分子机制非常重要。在本研究中，我们揭示了转录因子叉头盒 FOXK1 在乳腺癌中充当癌基因。我们发现 FOXK1 招募多种转录辅阻遏物复合物，包括 NCoR/SMRT、SIN3A、NuRD 和 REST/CoREST。其中，FOXK1/NCoR/SIN3A 复合体转录调节一组基因，包括 CLOCK、PER2 和 CRY2，这些基因与昼夜节律密切相关。该复合物通过扰乱昼夜节律振荡来促进乳腺癌细胞的增殖。值得注意的是，FOXK1的核表达与肿瘤分级呈正相关。随着肿瘤进展，胰岛素抵抗逐渐严重，并伴随着OGT表达增加，导致核易位和FOXK1表达增加。此外，我们发现二甲双胍下调 FOXK1 并将其从细胞核输出，而 HDAC 抑制剂 (HDACi) 抑制 FOXK1 相关酶活性。联合治疗通过FOXK1的调节增强生物钟基因的表达，从而发挥抗肿瘤作用，表明高核FOXK1表达的乳腺癌是二甲双胍和HDACi联合应用的潜在候选者。版权所有©2024。Elsevier B.V.出版。

The dysregulation of circadian rhythm oscillation is a prominent feature of various solid tumors. Thus, clarifying the molecular mechanisms that maintain the circadian clock is important. In the present study, we revealed that the transcription factor forkhead box FOXK1 functions as an oncogene in breast cancer. We showed that FOXK1 recruits multiple transcription corepressor complexes, including NCoR/SMRT, SIN3A, NuRD, and REST/CoREST. Among them, the FOXK1/NCoR/SIN3A complex transcriptionally regulates a cohort of genes, including CLOCK, PER2, and CRY2, that are critically involved in the circadian rhythm. The complex promoted the proliferation of breast cancer cells by disturbing the circadian rhythm oscillation. Notably, the nuclear expression of FOXK1 was positively correlated with tumor grade. Insulin resistance gradually became more severe with tumor progression and was accompanied by the increased expression of OGT, which caused the nuclear translocation and increased expression of FOXK1. Additionally, we found that metformin downregulates FOXK1 and exports it from the nucleus, while HDAC inhibitors (HDACi) inhibit the FOXK1-related enzymatic activity. Combined treatment enhanced the expression of circadian clock genes through the regulation of FOXK1, thereby exerting an antitumor effect, indicating that highly nuclear FOXK1-expressing breast cancers are potential candidates for the combined application of metformin and HDACi.Copyright © 2024. Published by Elsevier B.V.