Oncogenic Activity of E2F Transcription Factors
Most targets for chemotherapeutic intervention in cancer are the kinases. Presently, there is no way to target transcription factors. Elucidating the oncogenic mechanisms of the transcription factor E2F may open an opportunity for therapeutic intervention, but much more needs to be known about how this transcription factor drives cancer.
E2F is normally active during the S phase of the cell cycle. Ordinarily, these transcription factors are kept in check by the retinoblastoma (Rb) gene. Both E2F and Rb are ubiquitous in the body, and therefore affect cell replication everywhere. When Rb mutates, E2F becomes unchecked, resulting in uncontrolled cell division.
This cellular proliferation can result in the growth of tumors and metastasis. E2F is also involved in driving the proliferation of nondifferentiating stem cells in the marrow, contributing to bone marrow failure.
Using in vitro and mouse models in the laboratory, researchers at the Center for Childhood Cancer Research, led by Patrick M. Viatour, PharmD, PhD, are involved in long-term basic research investigating the non-cell cycle function that E2F plays in cancer; these functions may involve driving the metabolism of tumors, inhibiting apoptosis, increasing motility, or other effects that contribute to the hallmark characteristics of cancer.
Using liver cancer as a model, researchers have found that E2F during the progression of cancer remodels chromatin by recruiting the ATPases pontin and reptin. This ultimately amplifies E2F’s transactivational potential, resulting in increased self-proliferation of cells and activation of other oncogenic properties, such as the “rewiring” of glucose metabolism.
While targeting transcription factors therapeutically is not possible, targeting some of E2F’s downstream effects (such as the recruitment and binding of the chromatin regulators pontin and reptin) may be a possibility in the future. However, a clearer understanding of the non-cell cycle activities of E2F is necessary.
