By Daniel Walocha ‘19

FOXO proteins have previously been established as transcription factors in genes controlling mitogenic cell growth, metabolism, and proliferation. They contain a common sequence, the forkhead box, which encodes for a string of 80-100 amino acids which form a DNA-binding motif. Though, the specific cancer pathways and crosstalk among the signaling proteins have not been clearly described, Dr. Jian Ma and a team of researchers from the University of Pennsylvania have set out to encompass the important role of FOXO proteins in regulating cancer.

FOXO proteins are highly regulated in their expression, localization, and DNA binding. The FOXO proteins recognize the (G/C)(T/A)AA(C/T)AA consensus sequence at the enhancer of target genes. Upon binding, target genes such those who control apoptotic regulator Bcl-2 and insulin-like growth factor-binding protein 1 are activated, so regulation of FOXO transcription factors allow for key interference in cancer pathways. Among the regulatory proteins, AKT and PI3K are activated and lead to the subsequent phosphorylation of FOXO—sequestering the proteins to the cytoplasm and thereby inactivating them.  This phosphorylation also induces export of already-existing FOXO proteins out of the nucleus, ceasing transcription of growth factors, pro-survival, and proliferation effectors. Thus, a clear feedback mechanism is present in preventing overexpression of proto-oncogenes. Other key regulators involve ubiquitination and acetylation/methylation of the transcription factors. Mutations in the FOXO genes, which have clear anti-tumorigenic effects, lead to a higher occurrence in cancer cells.

FOXO proteins are generally thought to have a clear, anti-cancer role in cells, but some research in gastric cancers presented conflicting evidence. Further research is needed to understand the large influence this class of transcription factors play in cancer metabolism and growth. The transcription factors may also constitute a key therapeutic target if normal, non-cancerous cell metabolism is shown to be unaffected in future studies.

References:

1. J. Ma, et al., FOXO family in regulating cancer and metabolism. Seminars in Cancer Biology 47, (2018). doi: 10.1016/j.semcancer.2018.01.018.
2. Image retrieved from: https://en.m.wikipedia.org/wiki/File:PDB_2fo1_EBI.jpg