FOXM1: A small fox that makes more tracks for cancer progression and metastasis

Abstract

Transcription factors (TFs) are indispensable for the modulation of various signaling pathways associated with normal cell homeostasis and disease conditions. Among cancer-related TFs, FOXM1 is a critical molecule that regulates multiple aspects of cancer cells, including growth, metastasis, recurrence, and stem cell features. FOXM1 also impact the outcomes of targeted therapies, chemotherapies, and immune checkpoint inhibitors (ICIs) in various cancer types. Recent advances in cancer research strengthen the cancer-specific role of FOXM1, providing a rationale to target FOXM1 for developing targeted therapies. This review compiles the recent studies describing the pivotal role of FOXM1 in promoting metastasis of various cancer types. It also implicates the contribution of FOXM1 in the modulation of chemotherapeutic resistance, antitumor immune response/immunotherapies, and the potential of small molecule inhibitors of FOXM1.

Keywords: Chemoresistance; Metastasis; Recurrence; Subtype switching; Transcription factors.

Figure 1:. The structural organization of FOXM1 DNA binding domains and mechanisms regulating FOXM1.

(A) Domain wise arrangement for different splicing isoforms of FOXM1. (B) Three-dimensional structural organization of FOXM1 winged-helix-DNA binding domain interacting with the gene promoter. (C) Amino acids residues of FOXM1 showing binding with the nucleotides of DNA helix domain. (D) Cartoon (FOXM1 DNA-binding domain) and ball-stick model (DNA-binding amino acid residues) that could be targeted or utilized for developing small molecule inhibitors to block FOXM1: DNA interactions/binding. The structure coordinates were taken from PDBID:7FJ2. (E) Overview of major signaling pathways regulating FOXM1 expression and inhibition.

Figure 2:. FOXM1-associated pathways involved in metastasis, cancer growth and chemoresistance.

(A) FOXM1-mediated metastatic signaling pathways. The estrogen receptor (ER) or human epidermal growth factor receptor 2 (HER2), CXCR4, and TGFβR activates FOXM1 through various pathways such as ERK1/2, SMAD, STAT, and PI3K. Inactivation or deletion of p53/Rb1 also activates FOXM1. The activated FOXM1 translocate to the nucleus and increased the expression of genes associated with epithelial-to-mesenchymal transition (EMT) and angiogenesis such as Snail, Slug, MMPs, VEGF, Zeb-1 that enhances metastasis. (B) FOXM1 upregulation increases cancer cell survival and growth through PLK1, AURKB, DLX1, and CDKs. (C) Modulation of gene expression by FOXM1 infers drug-/chemo-resistance and alteration of immune landscape. FOXM1 activation increases the expression of genes associated with stem cell maintenance such as SOX2, stathmin, UHRF1. It also increased the expression of ABC transporters and PD-L1, the major regulators for chemo-/immuno-therapeutic antitumor response.