Friday, November 22, 2024
11/22/2024
My lab is focused on understanding the molecular events that result in the transition of a skeletal muscle precursor cell to a rhabdomyosarcoma (RMS) tumor cell in hopes to suggest therapeutic strategies to reduce the oncogenic potential of this childhood cancer. We have discovered that TBX2, a T-box family member, is a novel oncogene in RMS tumor cells. TBX2 is often over expressed in cancer cells and is thought to function in bypassing cell growth control by the repression of p14ARF and p21. The cell cycle regulator p21 is required for the terminal differentiation of skeletal muscle cells and is silenced in RMS cells. We have found that TBX2 represses p21, p14ARF and the tumor suppressor PTEN in RMS cells and inhibits the activity of the myogenic regulatory factors through binding to MYOG and MYOD1. Thus, TBX2 both promotes proliferation and represses terminal differentiation. Given the crucial importance of TBX2 in driving tumor cell proliferation in RMS, it is important to understand the regulation of TBX2. In other cells, TBX2 is regulated by PAX3, a paired- box transcription factor essential in skeletal muscle progenitor cells. RMS cells are characterized by expression of PAX3 and the more aggressive subtype of RMS contains a translocation that fuses PAX3 with the transactivation domain of a forkhead transcription factor producing a PAX3-FOXO1 fusion protein. FGF signaling has been shown to activate both PAX3 and TBX2 in other systems, suggesting that this may occur in skeletal muscle as well. We have also found that the highly related T-Box factor, TBX3, represses TBX2 in normal skeletal muscle and RMS, but TBX3 is itself silenced by the polycomb repressive complex (PRC2) in RMS. Our data suggest that TBX2 is part of the normal regulatory program expressed in proliferating myoblasts which is silenced in differentiated cells during development. The goal of this proposal is to investigate the regulation and additional gene targets of TBX2 in RMS cells, which will provide the needed molecular insight to potentially harness the expression or function of TBX2 therapeutically. In our first aim, we will identify mechanisms regulating TBX2 expression by determining if PAX3/PAX-FOXO1 and the FGF signaling pathway activate TBX2. In the second aim, we will characterize novel tumor suppressor genes regulated by TBX2 including TP53 and TCEAL7. P53 is a well known tumor suppressor that has been extensively studied in RMS, but our data are the first to implicate TBX2 in the silencing of TP53 in any system and suggest that TP53 is transcriptionally silenced in ARMS. The function of TCEAL7 is unexplored in RMS and may represent a novel therapeutic target. Finally, we will profile TBX2 binding on the genome to identify all genes bound by TBX2 in RMS. Taken together, this work will provide essential insight into the role and regulation of the novel oncogene TBX2 in RMS cells, thus providing a novel therapeutic target for RMS. Understanding abnormalities in gene regulatory pathways is crucial for understanding the pathology of cancer cells and for designing effective therapeutic strategies to improve treatment of rhabdomyosarcoma.
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