Emerging Roles of Forkhead Box Protein FoxM1 in Cancer: Implications in Tumorigenicity and Drug Therapy
thesisposted on 28.06.2013 by Zebin Wang
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FoxM1 belongs to the Forkhead Box (Fox) superfamily of transcriptional factors. It is a proliferative specific transcriptional regulator that is expressed during embryogenesis and in the progenitor population of normal tissue. Its expression is diminished in terminally differentiated cells. FoxM1 overexpression is commonly observed in many types of human malignancies. It participates in various cellular events that promote tumorigenesis and metastasis of the cancer cells. I discovered that FoxM1 is involved in promoting tumorigenicity by maintaining the undifferentiated status of the cancer cell. FoxM1 is overexpressed in neuroblastoma, a childhood malignancy derived from developing neural crust tissue. I found that FoxM1 is essential for the tumorigenicity of neuroblastoma cell in vitro and in vivo. Its presence is required for neuroblastoma to maintain the undifferentiated state and the cells are more resistant to differentiation stimuli. FoxM1 is able to activate the expression of the pluripotency genes SOX2 and Bmi1, which are involved in maintaining the undifferentiated status of the progenitor cells. In addition, in neural stem/progenitor cells, FoxM1 loss results in the reduction in self-renewal accompanied by attenuated expression of SOX2 and Bmi1. Targeting FoxM1 represents a rational and promising anti-cancer therapeutic strategy. A cell penetrating ARF 26-44 peptide which consists of 9 N-terminal D-arginine (D-Arg) residues and amino acid residues 26-44 of the mouse ARF protein was synthesized and proved to be effective in diminishing HCC tumor size in HCC and preventing metastasis in mouse model. I discovered that FoxM1 is critical for the survival and growth of p53-/- tumor cells both in vitro and in vivo. By inhibiting FoxM1 activity, ARF peptide effectively reduces the colonization of p53 -/- tumor cells in vivo accompanied by the induction of apoptosis. The FoxM1 target genes Survivin and Bmi1 are down regulated in ARF peptide treated cells and in colonized tumors. These observations validate the therapeutic strategy of targeting FoxM1 in tumors with p53 loss of function. I also established a connection between EZH2 and forkhead box transcription factor FoxM1 during prostate cancer progression. EZH2 expression is positively correlated with FoxM1 in prostate cancer patient samples. The expression of both genes increase gradually as prostate cancer progress to more advanced stages. In prostate cancer cells, the presence of FoxM1 is necessary for the expression of EZH2 and the repression of its target genes DAB2IP and E-cadherin. By modulating EZH2 expression, FoxM1 modulates the invasiveness and migration, which contribute to metastasis.