FOXO4 Target Gene Identification and Downstream PI3K Signaling in Glioblastoma

Glioblastoma Multiforme (GBM) is an aggressive cancer with patients surviving 13 months on average after diagnosis. Forkhead box transcription factors (FOXO1, FOXO3, and FOXO4) drive stem gene expression to promote growth and survival in GBM cells. We disrupted the FOXO4 gene in U87MG cells using CRISPR Cas9 genome editing and performed RNA Seq to identify targets of this transcription factor. 2,519 genes were differentially expressed in FOXO4 disruption mutants compared to wild-type U87MG control cells. FOXO4 loss led to significantly reduced LIF and SESN3 gene expression. Both LIF and SESN3 promote PI3K Pathway output. Based on this, we examined PI3K output by assessing AKT activation and discovered a two-fold reduction in FOXO4 disruption mutants. Current efforts are aimed at determining whether LIF and/or SESN3 promote AKT activation in GBM cells. In addition, other impacts that LIF and SESN3 may have on GBM cells are being examined. This study highlights novel roles for FOXO4 in GBM that may lead to cancer aggressiveness by increasing PI3K Pathway activity. This work was supported by NIH 1SC3GM132053-03 (M.K.), and UTRGV Presidential Research Scholarship (D.U.).