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.

FOXO3a and FOXM1 are two forkhead transcription factors with antagonistic roles in cancer and DNA damage response. FOXO3a functions like a typical tumour suppressor, whereas FOXM1 is a potent oncogene aberrantly overexpressed in genotoxic resistant cancers. FOXO3a not only represses FOXM1 expression but also its transcriptional output. Recent research has provided novel insights into a central role for FOXO3a and FOXM1 in DNA damage response. The FOXO3a-FOXM1 axis plays a pivotal role in DNA damage repair and the accompanied cellular response through regulating the expression of genes essential for DNA damage sensing, mediating, signalling and repair as well as for senescence, cell cycle and cell death control. In this manner, the FOXO3a-FOXM1 axis also holds the key to cell fate decision in response to genotoxic therapeutic agents and controls the equilibrium between DNA repair and cell termination by cell death or senescence. As a consequence, inhibition of FOXM1 or reactivation of FOXO3a in cancer cells could enhance the efficacy of DNA damaging cancer therapies by decreasing the rate of DNA repair and cell survival while increasing senescence and cell death. Conceptually, targeting FOXO3a and FOXM1 may represent a promising molecular therapeutic option for improving the efficacy and selectivity of DNA damage agents, particularly in genotoxic agent resistant cancer. In addition, FOXO3a, FOXM1 and their downstream transcriptional targets may also be reliable diagnostic biomarkers for predicting outcome, for selecting therapeutic options, and for monitoring treatments in DNA-damaging agent therapy.

Forkhead box (FOX) transcription factors compose a large family of regulators of key biological processes within a cell. FOXK2 is a member of FOX family, whose biological functions remain relatively unexplored, despite its description in the early nineties. More recently, growing evidence has been pointing towards a role of FOXK2 in cancer, which is likely to be context-dependent and tumour-specific. Here, we provide an overview of important aspects concerning the mechanisms of regulation of FOXK2 expression and function, as well as its complex interactions at the chromatin level, which orchestrate how it differentially regulates the expression of gene targets in pathophysiology. Particularly, we explore the emerging functions of FOXK2 as a regulator of a broad range of cancer features, such as cell proliferation and survival, DNA damage, metabolism, migration, invasion and metastasis. Finally, we discuss the prognostic value of assessing FOXK2 expression in cancer patients and how it can be potentially targeted for future anticancer interventions.