Foxd1, a member of the forkhead box (FOX) family of transcription factors, contains a winged helix-turn-helix DNA-binding motif. It is involved in multiple key biological processes such as kidney and retina development, embryo implantation, and cell cycle regulation, metabolism control, and stem cell niche maintenance [4].

In pancreatic cancer, FOXD1 mRNA and protein are upregulated, and high expression is linked to poor prognosis. Overexpression promotes aerobic glycolysis, proliferation, invasion, and metastasis, while knockdown inhibits these functions. Mechanistically, FOXD1 directly promotes SLC2A1 transcription and inhibits its degradation, enhancing GLUT1-mediated aerobic glycolysis [1]. In breast cancer, high FOXD1 expression in primary tissues is associated with increased circulating tumor cells (CTCs). FOXD1 promotes CTC formation and metastasis via the RalA-ANXA2-Src complex, which activates the ERK1/2 signal [2]. In uveal melanoma, FOXD1 expression is negatively correlated with survival, and it may promote tumor growth and invasion [3]. In prostate cancer, FOXD1 is upregulated, and its knockdown inhibits cell viability, migration, and invasion. It is positively regulated by LMNB1 and may serve as an oncogene [5]. In oral squamous cell carcinoma, FOXD1-AS1 upregulates FOXD1 to promote tumor progression [6]. In head and neck carcinoma, FOXD1 promotes cell proliferation by blocking cellular senescence and apoptosis through the p21/CDK2/Rb signaling pathway, and miR-30e-5p can suppress FOXD1 translation [7].

In summary, Foxd1 plays diverse and crucial roles in development and disease. Gene knockout or knockdown studies in various cancer models have revealed its oncogenic potential in multiple cancers, suggesting it could be a potential therapeutic target in pancreatic, breast, uveal, prostate, oral, and head-and-neck cancers. Understanding Foxd1's functions through these model-based studies is essential for developing new strategies against these diseases.

References:

1. Cai, Kun, Chen, Shiyu, Zhu, Changhao, He, Zhiwei, Sun, Chengyi. 2022. FOXD1 facilitates pancreatic cancer cell proliferation, invasion, and metastasis by regulating GLUT1-mediated aerobic glycolysis. In Cell death & disease, 13, 765. doi:10.1038/s41419-022-05213-w. https://pubmed.ncbi.nlm.nih.gov/36057597/

2. Long, Yufei, Chong, Tuotuo, Lyu, Xiaoming, Chen, Ceshi, Li, Xin. 2022. FOXD1-dependent RalA-ANXA2-Src complex promotes CTC formation in breast cancer. In Journal of experimental & clinical cancer research : CR, 41, 301. doi:10.1186/s13046-022-02504-0. https://pubmed.ncbi.nlm.nih.gov/36229838/

3. Luo, Yang, Ni, Renhao, Jin, Xiaojun, Yang, Lu, Zhu, Yabin. 2023. FOXD1 expression-based prognostic model for uveal melanoma. In Heliyon, 9, e21333. doi:10.1016/j.heliyon.2023.e21333. https://pubmed.ncbi.nlm.nih.gov/38027647/

4. Quintero-Ronderos, Paula, Laissue, Paul. 2018. The multisystemic functions of FOXD1 in development and disease. In Journal of molecular medicine (Berlin, Germany), 96, 725-739. doi:10.1007/s00109-018-1665-2. https://pubmed.ncbi.nlm.nih.gov/29959475/

5. Huang, Yuanshe, Zhang, Lai, Liu, Tianlei, Liang, E. 2023. LMNB1 targets FOXD1 to promote progression of prostate cancer. In Experimental and therapeutic medicine, 26, 513. doi:10.3892/etm.2023.12212. https://pubmed.ncbi.nlm.nih.gov/37840569/

6. Ma, Yuxin, Han, Jingchao, Luo, Xi. 2021. FOXD1-AS1 upregulates FOXD1 to promote oral squamous cell carcinoma progression. In Oral diseases, 29, 604-614. doi:10.1111/odi.14002. https://pubmed.ncbi.nlm.nih.gov/34403535/

7. Wu, Tong, Yang, Zhongyuan, Chen, Weichao, Song, Ming, Yang, Ankui. 2023. miR-30e-5p-mediated FOXD1 promotes cell proliferation by blocking cellular senescence and apoptosis through p21/CDK2/Rb signaling in head and neck carcinoma. In Cell death discovery, 9, 295. doi:10.1038/s41420-023-01571-2. https://pubmed.ncbi.nlm.nih.gov/37563111/