Investigating the protective role of FOXM1 against oxidative stress and DNA damage in human embryonic stem cells

Abstract

Human embryonic stem cells (hESCs) hold immense potential for tissue engineering and regenerative medicine. For hESCs to function properly, it is hypothesized that they posses stringent mechanisms to maintain genome integrity. The Forkhead box transcription factor FOXM1 is ubiquitously expressed in embryonic tissues that are highly proliferative and regenerative. Recent studies have shown that FOXM1 is critically required for protection against cellular senescence and as a mediator of the DNA damage response. In human primary fibroblasts, FOXM1 regulates the expression of antioxidant enzymes, including MnSOD and catalase, which defend against reactive oxygen species. DNA repair genes like BRIP1 and RAD51 have recently been shown to be the transcriptional targets of FOXM1. We hypothesized that FOXM1 is a critical regulator for maintaining genome stability in hESCs. In this study, FOXM1 was found to be expressed at high levels in the hESC cell line VAL-3. Knockdown of FOXM1 in VAL-3 cells using specific siRNAs reduced proliferation but did not affect pluripotency. Moreover, FOXM1-depleted VAL-3 cells became sensitized to oxidative stress. Interestingly, comparison of mRNA and protein levels suggested that the FOXM1 protein was stabilized upon hydrogen peroxide treatment. These findings suggest that FOXM1 may play a role in protecting hESCs against oxidative stress. Further studies will be conducted to explore whether FOXM1 is also required for protecting against other genotoxic stresses and the downstream transcriptional targets involved.