2. Academic Validation
  3. Forkhead box protein FOXK1 disrupts the circadian rhythm to promote breast tumorigenesis in response to insulin resistance

Forkhead box protein FOXK1 disrupts the circadian rhythm to promote breast tumorigenesis in response to insulin resistance

  • Cancer Lett. 2024 Sep 1:599:217147. doi: 10.1016/j.canlet.2024.217147.
Zhaohan Zhang 1,  Minghui Zhao 1,  Qian Wang 2,  Xilin Wang 1,  Yu Wang 1,  Yuze Ge 1,  Zicheng Wu 1,  Wenjuan Wang 3,  Lin Shan 4
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China.
  • 2 Department of Tumor Cell Biology, Tianjin Medical University Cancer Institute, and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, 300060, Tianjin, China; National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, 300060, Tianjin, China.
  • 3 Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China; Beijing Key Laboratory of Cancer Invasion and Metastasis Research, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China.
  • 4 Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China; Beijing Key Laboratory of Cancer Invasion and Metastasis Research, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China. Electronic address: shanlin@ccmu.edu.cn.
PMID: 39094826 DOI: 10.1016/j.canlet.2024.217147
Abstract

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.

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