TBX2 blocks myogenesis and promotes proliferation in rhabdomyosarcoma cells

Abstract

Rhabdomyosarcomas (RMS) are the most frequent soft tissue sarcomas in children that share many features of developing skeletal muscle. We have discovered that a T-box family member, TBX2, is highly up regulated in tumor cells of both major RMS subtypes. TBX2 is a repressor that is often over expressed in cancer cells and is thought to function in bypassing cell growth control, including repression of p14 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 interacts with the myogenic regulatory factors MyoD and myogenin and inhibits the activity of these factors. TBX2 is expressed in primary myoblasts and C2C12 cells, but is strongly down regulated upon differentiation. TBX2 recruits the histone deacetylase HDAC1 and is a potent inhibitor of the expression of muscle specific genes and the cell cycle regulators, p21 and p14. TBX2 promotes the proliferation of RMS cells and either depletions of TBX2 or dominant negative TBX2 up regulate p21 and muscle specific genes. Significantly, depletion or interference with TBX2 completely inhibits tumor growth in a xenograft assay, highlighting the oncogenic role of TBX2 in RMS cells. Thus, the data demonstrate that elevated expression of TBX2 contributes to the pathology of RMS cells by promoting proliferation and repressing differentiation specific gene expression. These results show that deregulated TBX2 serves as an oncogene in RMS, suggesting that TBX2 may serve as a new diagnostic marker or therapeutic target for RMS tumors.

Alternative Splicing of MEF2C pre-mRNA Controls Its Activity in Normal Myogenesis and Promotes Tumorigenicity in Rhabdomyosarcoma Cells

“…The following antibodies were used: HDAC5 (Cell Signaling Technology), HDAC4 (Cell Signaling Technology), and rabbit IgG (Santa Cruz Biotechnology) as a nonspecific control. Primers corresponding to the LMOD2 and CDKN1A promoters were as described previously (32 …”

The role of T-box genes in the tumorigenesis and progression of cancer

“…A recent study by Zhu et al (35) identified that TBX2 was highly upregulated in tumor cells of the major RMS subtypes. The results of this study demonstrated that elevated expression of TBX2 contributes to the pathology of RMS cells.…”

“…The results of this study demonstrated that elevated expression of TBX2 contributes to the pathology of RMS cells. TBX2 inhibited the regulatory factors myogenic differentiation 1 and myogenin, leading to the promotion of proliferation (35). Furthermore, TBX2 recruited the histone deacetylase HDAC1 and inhibited p21, which led to increased proliferation and decreased differentiation-specific gene expression (35).…”

“…TBX2 inhibited the regulatory factors myogenic differentiation 1 and myogenin, leading to the promotion of proliferation (35). Furthermore, TBX2 recruited the histone deacetylase HDAC1 and inhibited p21, which led to increased proliferation and decreased differentiation-specific gene expression (35). Depletion or inhibition of TBX2 completely inhibited tumor cell growth in RMS cells (35).…”

“…Furthermore, TBX2 recruited the histone deacetylase HDAC1 and inhibited p21, which led to increased proliferation and decreased differentiation-specific gene expression (35). Depletion or inhibition of TBX2 completely inhibited tumor cell growth in RMS cells (35). These results indicate that deregulated TBX2 serves as an oncogene in RMS, and may be a novel diagnostic marker and/or therapeutic target in patients with RMS.…”