title: FOXM1 in sarcoma: role in cell cycle, pluripotency genes and stem cell pathways.
abstract: FOXM1 is a pro-proliferative transcription factor that promotes cell cycle progression at the G1-S, and G2-M transitions. It is activated by phosphorylation usually mediated by successive cyclin - cyclin dependent kinase complexes, and is highly expressed in sarcoma. p53 down regulates FOXM1 and FOXM1 inhibition is also partly dependent on Rb and p21. Abnormalities of p53 or Rb are frequent in sporadic sarcomas with bone or soft tissue sarcoma, accounting for 36% of index cancers in the high penetrance TP53 germline disorder, Li-Fraumeni syndrome.FOXM1 stimulates transcription of pluripotency related genes including SOX2, KLF4, OCT4, and NANOG many of which are important in sarcoma, a disorder of mesenchymal stem cell/ partially committed progenitor cells. In a selected specific, SOX2 is uniformly expressed in synovial sarcoma. Embryonic pathways preferentially used in stem cell such as Hippo, Hedgehog, and Wnt dominate in FOXM1 stoichiometry to alter rates of FOXM1 production or degradation. In undifferentiated pleomorphic sarcoma, liposarcoma, and fibrosarcoma, dysregulation of the Hippo pathway increases expression of the effector co-transcriptional activator Yes-Associated Protein (YAP). A complex involving YAP and the transcription factor TEAD elevates FOXM1 in these sarcoma subtypes. In another scenario 80% of desmoid tumors have nuclear localization of β-catenin, the Wnt pathway effector molecule. Thiazole antibiotics inhibit FOXM1 and because they have an auto-regulator loop FOXM1 expression is also inhibited. Current systemic treatment of sarcoma is of limited efficacy and inhibiting FOXM1 represents a potential new strategy.
authors.affiliation: St. James Hospital, Dublin, Ireland.|Trinity College Dublin, Dublin, Ireland.
authors.forename: Fergal C
authors.initials: FC
authors.lastname: Kelleher
authors.affiliation: Whangarei Base Hospital, Whangarei, New Zealand.
authors.forename: Hazel
authors.initials: H
authors.lastname: O'Sullivan
mesh_terms: D000818:Animals; D002453:Cell Cycle; D049109:Cell Proliferation; D015536:Down-Regulation; D000072278:Forkhead Box Protein M1 / Q000378:metabolism*; D006801:Humans; D000090062:Kruppel-Like Factor 4; D008648:Mesoderm / Q000378:metabolism; D010766:Phosphorylation; D016160:Retinoblastoma Protein / Q000378:metabolism; D012509:Sarcoma / Q000378:metabolism*; D012983:Soft Tissue Neoplasms / Q000378:metabolism*; D013234:Stem Cells / Q000378:metabolism*; D013844:Thiazoles / Q000737:chemistry; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4; D016160:Retinoblastoma Protein; C495901:TP53 protein, human; D013844:Thiazoles; D016159:Tumor Suppressor Protein p53
keywords: DREAM; FOXM1; mesenchyme; pluripotency genes; thiazole antibiotics