Research Paper Volume 8, Issue 7 pp 1384—1397

FOXM1 regulates proliferation, senescence and oxidative stress in keratinocytes and cancer cells

Artem Smirnov1, , Emanuele Panatta1, , AnnaMaria Lena1, , Daniele Castiglia2, , Nicola Di Daniele3, , Gerry Melino1, , Eleonora Candi1,2, ,

  • 1 University of Rome “Tor Vergata,” Department of Experimental Medicine and Surgery, 00133, Rome, Italy
  • 2 Istituto Dermopatico dell'Immacolata (IDI-IRCCS), 00166, Rome, Italy
  • 3 University of “Tor Vergata”, Department of Systems Medicine, 00133, Rome, Italy

Received: April 28, 2016       Accepted: June 12, 2016       Published: July 3, 2016      

https://doi.org/10.18632/aging.100988
How to Cite

Copyright: © 2016 Smirnov et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Several transcription factors, including the master regulator of the epidermis, p63, are involved in controlling human keratinocyte proliferation and differentiation. Here, we report that in normal keratinocytes, the expression of FOXM1, a member of the Forkhead superfamily of transcription factors, is controlled by p63. We observe that, together with p63, FOXM1 strongly contributes to the maintenance of high proliferative potential in keratinocytes, whereas its expression decreases during differentiation, as well as during replicative-induced senescence. Depletion of FOXM1 is sufficient to induce keratinocyte senescence, paralleled by an increased ROS production and an inhibition of ROS-scavenger genes (SOD2, CAT, GPX2, PRDX). Interestingly, FOXM1 expression is strongly reduced in keratinocytes isolated from old human subjects compared with young subjects. FOXM1 depletion sensitizes both normal keratinocytes and squamous carcinoma cells to apoptosis and ROS-induced apoptosis. Together, these data identify FOXM1 as a key regulator of ROS in normal dividing epithelial cells and suggest that squamous carcinoma cells may also use FOXM1 to control oxidative stress to escape premature senescence and apoptosis.

Abbreviations

FOXM1: forkhead box protein M1; ROS: reactive oxygen species; TF: transcription factor; SOD2: manganese superoxide dismutase 2; CAT: catalase; GPX2: glutathione peroxidase 2; PRDX: peroxiredoxin; K14 (KRT14): Keratin 14; K10 (KRT10): Keratin 10; RE: response element; NHEK: normal human epidermal keratinocyte; Rb: retinoblastoma protein.