FOXM1: An emerging master regulator of DNA damage response and genotoxic agent resistance

Abstract

FOXM1 is a transcription factor required for a wide spectrum of essential biological functions, including DNA damage repair, cell proliferation, cell cycle progression, cell renewal, cell differentiation and tissue homeostasis. Recent evidence suggests that FOXM1 also has a role in many aspects of the DNA damage response. Accordingly, FOXM1 drives the transcription of genes for DNA damage sensors, mediators, signal transducers and effectors. As a result of these functions, it plays an integral part in maintaining the integrity of the genome and so is key to the propagation of accurate genetic information to the next generation. Preserving the genetic code is a vital means of suppressing cancer and other genetic diseases. Conversely, FOXM1 is also a potent oncogenic factor that is essential for cancer initiation, progression and drug resistance. An enhanced FOXM1 DNA damage repair gene expression network can confer resistance to genotoxic agents. Developing a thorough understanding of the regulation and function of FOXM1 in DNA damage response will improve the diagnosis and treatment of diseases including cancer, neurodegenerative conditions and immunodeficiency disorders. It will also benefit cancer patients with acquired genotoxic agent resistance.

Unravelling the role of fatty acid metabolism in cancer through the FOXO3-FOXM1 axis

“…FOXO3 and FOXM1 have antagonistic functions in the regulation of their target genes and this axis can modulate chemotherapy resistance (Zhao and Lam, 2012;Bella et al, 2014). FOXM1 has also been demonstrated to play a crucial role in cancer chemotherapeutic drug resistance Lam, 2007, 2008;Zona et al, 2014;Zhao and Lam, 2012;Bella et al, 2014;Chen et al, 2010). Insulin-like growth factor (IGF)-I also up-regulates the expression and activity of Foxm1 …”

“…Conversely, another Forkhead protein FOXM1 behaves as a classic potent oncogene (Myatt and Lam, 2007;Gomes et al, 2013). An increase in its expression or activity promotes three key features of cancer: cell transformation, tumour progression and resistance to cytotoxic agents Lam, 2007, 2008;Zona et al, 2014). Notably, FOXM1 is a transcriptional target repressed by FOXO proteins and thus a downstream effector of the PI3K-AKT-FOXO axis .…”

Expression profiling of small intestinal neuroendocrine tumors identifies subgroups with clinical relevance, prognostic markers and therapeutic targets

“…FOXM1 is an oncogenic transcription factor promoting cell cycle progression and resistance to genotoxic drugs. 36,37 Recently, a strong association between FOXM1 and metastases was reported for gastroenteropancreatic neuroendocrine tumors. 38 Therapies targeting FOXM1 are under way, and may be considered in the future.…”

FOXM1 regulates glycolysis in hepatocellular carcinoma by transactivating glucose transporter 1 expression

“…The expression of FOXM1 is frequently upregulated in many solid tumors (7). The overexpression of FOXM1 promotes proliferation, invasion and epithelial-mesenchymal transition, and is associated with a poor prognosis in HCC (8)(9)(10).…”