The Homeobox Genes: Classification, Regulation, Biological Functions, and Diseases

ABSTRACT Homeobox genes constitute a large family of transcription factors that act as master regulators involved in multiple fundamental processes such as development and cell differentiation. Consequently, these transcription factors perform diverse functions throughout human life. However, dysregulation of homeobox gene expression, through pathogenic variants or epigenetic alterations, has been increasingly associated with a wide range of human disorders. In particular, correlations between homeobox genes and various types of cancer have been documented in hundreds of studies. This review provides an integrative overview of homeobox gene biology, summarizing their classification as well as their physiological and pathological roles across noncancerous and cancerous diseases. Particular attention is given to how dysregulation of gene expression contributes to various noncancerous diseases (e.g., congenital, metabolic, and neurodegenerative disorders) and to malignancies, especially the five highest incidence of cancers, with a detailed focus on lung cancer, where epigenetic mechanisms play a central role in tumor progression.