Pathology

E-mail: dean.tantin@path.utah.edu
Address: JMRB Rm 5700B
Phone: 587-3035

Cancer, metabolism, and stem cell function: the role of Oct transcription factors

Project 1: Interference with tumor metabolism can both prevent tumor onset and reduce tumor growth. We have found that loss of the transcription factor Oct1 induces specific metabolic alterations, and antagonizes transformation in vitro and tumorigenicity in vivo. Loss of Oct1 also makes cells hypersensitive to ionizing radiation and chemotherapeutics such as doxorubicin. We have found that Oct1 responds to stress signals to alter gene expression through a novel mechanism involving binding to complex DNA sites. We are testing the hypothesis that Oct1 responds to metabolic stresses to coordinate a program of gene expression that alters metabolism and tumorigenicity. Project 2: A recent development has been the emergence of the “tumor stem cell” concept. In embryonic stem cells, the transcription factor Oct4 is known to be a master regulator of “stemness”. Oct1, which is expressed in most adult tissues, has a nearly identical DNA binding domain and identical DNA binding specificity as Oct4. Further, Oct1 and Oct4 have numerous overlapping targets. Although not stem cells, loss of Oct1 in primary murine fibroblasts leads to a decrease in the “stemness” gene expression signature. These results suggest that 1) stemness is not an all-or-nothing phenomenon and 2) like the closely related Oct4 transcription factor, Oct1 can regulate stem cell identity. We will test the possibility that Oct1 regulates stemness in adult cells through the control of metabolism. This project integrates the burgeoning fields of tumor metabolism and tumor stem cells. Project 3: Despite the high profile of proteins such as Oct4, next to nothing is known about the actual mechanism by which Oct proteins regulate gene expression. We have identified a role for these proteins in regulating DNA methylation, and hypothesize that these factors act by stabilizing an unmethylated state. We are working to unravel the mechanism. Because Oct1 proteins are expressed in many tissues but are particularly well associated with early embryonic development, the central nervous system, the immune system, and cancer, understanding the biology of this group of transcription factors will shed light on all of these processes.

1/2008