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.
Highlights
Soft tissue sarcomas are heterogeneous mesenchymal tumors
Cyclin/CDK complexes mediate cell cycle progression with their effects partly executed by altering transcription factors such as Forkhead Box M1 (FOXM1) or E2F
A suggested inference is that FOXM1 has a similar role in undifferentiated pleomorphic sarcoma. It is a diagnosis of exclusion as these tumors defy lineage assignment. This postulate is partly substantiated by recent experimental evidence in which deregulated Hippo pathway signaling in soft-tissue sarcomas was found to promote FOXM1 expression and tumorigenesis in undifferentiated pleomorphic sarcoma, fibrosarcoma and liposarcoma [31]
Summary
Soft tissue sarcomas are heterogeneous mesenchymal tumors. The American Cancer Society in 2015 documented an incidence rate of 11,930, with an anticipated annual death rate of 4,870. FOXM1 transcriptionally activates important pro-proliferative genes and promotes cell cycle progression at the G1/S and G2/M transitions. Cyclin/CDK complexes mediate cell cycle progression with their effects partly executed by altering transcription factors such as FOXM1 or E2F. CDK4/6 stabilized and activated FOXM1, thereby maintaining G1/S phase gene expression and suppressing reactive oxygen species levels.
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