FOXM1

What is FOXM1 protein?

FOXM1 gene (forkhead box M1) is a protein coding gene which situated on the short arm of chromosome 12 at locus 12p13. FOXM1 is a transcription factor belonging to the Forkhead box (FOX) protein superfamily with a conserved coiled DNA binding domain. FOXM1 plays a role in multiple phases of the cell cycle, including cell proliferation, self-renewal, and tumorigenesis. It regulates the expression of target genes by transcription, and FOXM1 is overexpressed in a variety of human cancers, and this often predicts a poor prognosis for cancer patients. FOXM1 is able to maintain the characteristics of cancer by regulating the expression of target genes at the transcriptional level. Due to its potential role in cancer treatment, FOXM1 was named Molecule of the Year in 2010. The FOXM1 protein is consisted of 763 amino acids and FOXM1 molecular weight is approximately 84.3 kDa.

What is the function of FOXM1 protein?

FOXM1 acts as a transcriptional activator, controlling the expression of genes involved in cell cycle progression, DNA replication, and mitosis. It stimulates cell cycle progression by promoting entry into the S-phase and M-phase, and is essential for the execution of mitosis. FOXM1 is involved in the DNA damage response pathway, playing a role in maintaining genomic stability and chromosomal integrity. FOXM1 is essential for embryonic development, and its knockout results in embryonic lethality. FOXM1 is involved in maintaining stem cell pluripotency and self-renewal capacity. The expression and activity of FOXM1 are tightly regulated at multiple levels, including transcriptional, post-transcriptional, and post-translational modifications, as well as protein-protein and protein-RNA interactions.

Fig1. Regulation of FOXM1 expression in human prostate cancer. (Da Young Lee, 2024)

FOXM1 Related Signaling Pathway

FOXM1 plays an important role in DNA damage repair, maintaining genome integrity through transcriptional regulation of DNA damage sensors, mediators, signal transducers and effector molecules. This is essential for curbing cancer and other genetic diseases. FOXM1 plays a role in regulating metabolic pathways and influences the metabolic state of cells. For example, it affects insulin secretion and blood sugar control in diabetes by regulating the expression of genes associated with insulin secretion and insulin resistance. FOXM1 plays a role in cellular responses to stress, such as heat shock, oxidative stress, etc., protecting cells by forming stress particles (SGs). FOXM1 affects the fate of cells by regulating genes involved in apoptosis and survival. In some cases, FOXM1 expression can promote cell survival, while in other cases, it may promote apoptosis.

FOXM1 Related Diseases

FOXM1 protein has been implicated in a wide range of diseases due to its key role in a variety of pathological processes. In the field of cancer, overexpression of FOXM1 is closely associated with the development, progression, and poor prognosis of a variety of tumors, including ovarian, breast, prostate, liver, lung, colorectal, pancreatic, skin, cervical, ovarian, oral, blood, and nervous system tumors. In addition to its role in cancer, FOXM1 has been implicated in the occurrence and development of non-malignant diseases, particularly in diabetes, inflammation, pulmonary fibrosis, tissue repair and regeneration. In addition, FOXM1 also plays a role in tissue regeneration and repair, such as regulating cell proliferation and migration in liver regeneration.

Bioapplications of FOXM1

FOXM1 plays a regulatory role in the sensitivity of cancer cells to chemotherapy drugs, and its inhibition may enhance the response of cancer cells to conventional chemotherapy drugs and help overcome multidrug resistance in tumors. The expression level of FOXM1 is associated with patient prognosis in a variety of cancers, so it can be used as a potential biomarker for early diagnosis, risk assessment and prognostic judgment of cancer. FOXM1 plays a role in the process of tissue repair and regeneration, and its regulatory role may help improve wound healing and tissue regeneration strategies. The development of FOXM1 inhibitors, including small molecule compounds and biologics, provides new strategies for the treatment of cancer and other FOXM1-related diseases.

Case Study 1: Xiongfeng Chen, 2022

Forkhead box M1 (FOXM1) is a proliferative transcription factor and plays a vital role in many cancers. However, the function and molecular mechanism of FOXM1 in esophageal squamous cell carcinoma (ESCC) remain poorly understood. Hence, researchers aim to clarify the molecular basis of FOXM1-mediated ESCC progression. In this study, bioinformatics analysis showed that FOXM1 was mainly involved in key signal pathways, including cell proliferation, cell cycle, and homologous recombination in ESCC, and predicted that CDC6 might be a potential regulatory target gene of FOXM1. The results revealed that FOXM1 and CDC6 were significantly overexpressed in ESCC tissue and cell line, and their expression was positively correlated. Further studies showed that FOXM1 directly transcriptionally activated CDC6 by binding to its promoter region in ESCC cells. Moreover, FOXM1 mediated ESCC cell proliferation by regulating CDC6 expression, which may be related to promoting G1-S phase transition of cell cycle.

Fig1. mRNA and protein levels of FOXM1 and CDC6 were detected.

Fig2. The protein expression levels of FOXM1 and CDC6 were detected by western blot.

Case Study 2: Sang-Hoon Yi, 2014

The FOXM1 transcription factor is an oncoprotein and a top biomarker of poor prognosis in human cancer. Overexpression and activation of FOXM1 is frequent in high-grade serous carcinoma (HGSC), the most common and lethal form of human ovarian cancer, and is linked to copy number gains at chromosome 12p13.33. Researchers show that FOXM1 is co-amplified and co-expressed with RHNO1, a gene involved in the ATR-Chk1 signaling pathway that functions in the DNA replication stress response. They demonstrate that FOXM1 and RHNO1 are head-to-head genes (BDG) regulated by a bidirectional promoter (BDP) (named F/R-BDP). FOXM1 and RHNO1 each promote oncogenic phenotypes in HGSC cells, including clonogenic growth, DNA homologous recombination repair, and poly-ADP ribosylase inhibitor resistance. FOXM1 and RHNO1 are one of the first examples of oncogenic BDG, and therapeutic targeting of FOXM1/RHNO1 BDG is a potential therapeutic approach for ovarian and other cancers.

Fig3. FOXM1 and RHNO1 nuclear protein levels.

Fig4. OVCAR8 and CAOV3 cells were engineered for FOXM1 or RHNO1 CRISPR knockout.

FOXM1 has several biochemical functions, for example, DNA binding,RNA polymerase II transcription factor activity, sequence-specific DNA binding,protein binding. Some of the functions are cooperated with other proteins, some of the functions could acted by FOXM1 itself. We selected most functions FOXM1 had, and list some proteins which have the same functions with FOXM1. You can find most of the proteins on our site.

FOXM1 has direct interactions with proteins and molecules. Those interactions were detected by several methods such as yeast two hybrid, co-IP, pull-down and so on. We selected proteins and molecules interacted with FOXM1 here. Most of them are supplied by our site. Hope this information will be useful for your research of FOXM1.

CTNNB1;TCF7L2