MTBP and MYC: A Dynamic Duo in Proliferation, Cancer, and Aging

SIMPLE SUMMARY: Cancer is the second leading cause of death globally, accounting for approximately one in six deaths. Due to its critical role in cell growth/proliferation, one of the most well-known cancer-promoting proteins is MYC. Because cancer cells need MYC to grow, MYC is usually overactive in human cancers. However, despite decades of research, drugs targeting MYC continue to remain elusive. Notably, MYC requires other proteins to function properly. Our investigations into a protein named MTBP revealed that it associates with MYC and helps its pro-growth and cancer promoting function. Here, we discuss MTBP and review evidence showing MTBP is a critical partner for MYC, although the full extent of this partnership remains unresolved. We also discuss the role of MTBP in cancer, as MTBP levels are elevated in many human cancers and is often associated with reduced cancer patient survival. Additionally, we will discuss the inhibition of cancer cell growth and induction of cancer cell death by decreasing MTBP levels, indicating MTBP may represent a new cancer drug target and a way of indirectly targeting MYC. ABSTRACT: The oncogenic transcription factor c-MYC (MYC) is highly conserved across species and is frequently overexpressed or dysregulated in human cancers. MYC regulates a wide range of critical cellular and oncogenic activities including proliferation, metabolism, metastasis, apoptosis, and differentiation by transcriptionally activating or repressing the expression of a large number of genes. This activity of MYC is not carried out in isolation, instead relying on its association with a myriad of protein cofactors. We determined that MDM Two Binding Protein (MTBP) indirectly binds MYC and is a novel MYC transcriptional cofactor. MTBP promotes MYC-mediated transcriptional activity, proliferation, and cellular transformation by binding in a protein complex with MYC at MYC-bound promoters. This discovery provided critical context for data linking MTBP to aging as well as a rapidly expanding body of evidence demonstrating MTBP is overexpressed in many human malignancies, is often linked to poor patient outcomes, and is necessary for cancer cell survival. As such, MTBP represents a novel and potentially broad reaching oncologic drug target, particularly when MYC is dysregulated. Here we have reviewed the discovery of MTBP and the initial controversy with its function as well as its associations with proliferation, MYC, DNA replication, aging, and human cancer.