The Function of MTBP in Proliferation, Tumorigenesis and Tumor Cell Maintenance
Grieb, Brian Charles
Although the MYC transcription factor was discovered over three decades ago and is dysregulated in the majority of human cancers, its regulation remains incompletely understood and there is no pharmacologic means to inhibit its activity directly. My collaborators and I have identified the MYC transcriptional cofactors TIP48 and TIP49 and MYC as novel binding partners of MTBP, a functionally undefined protein that we show is oncogenic and overexpressed in many human cancers. MTBP associated with MYC through the highly conserved Myc Box II domain at gene promoters transcriptionally regulated by MYC, significantly enhancing MYC-mediated transcription, proliferation, and in vitro and in vivo transformation. In contrast, inhibition of MTBP using a dominant negative MTBP mutant impeded MYC activity and reduced proliferation of cancer cells. Overexpression of MTBP was associated with reduced breast cancer patient survival. Interestingly, MTBP levels were highest in triple negative breast cancers (TNBC), a clinically aggressive breast cancer subtype known to have elevated MYC transcriptional activity. Loss of MTBP expression in TNBC cells induced apoptosis, significantly impairing tumor cell growth, in vitro and in vivo. Thus, MTBP is a MYC transcriptional cofactor that functions with MYC to promote tumorigenesis and is necessary for cancer cell survival. The data suggest MTBP is a potential therapeutic target and an indirect means to inhibit MYC activity in the nearly 70% of human malignancies that overexpress MYC.