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

## TL;DR

This review summarizes the biology of homeobox genes and their roles in development, disease, and cancer, focusing on dysregulation and epigenetic mechanisms.

## Contribution

An integrative overview of homeobox gene biology and their roles in both noncancerous and cancerous diseases.

## Key findings

- Homeobox genes are master regulators in development and cell differentiation.
- Dysregulation of homeobox genes is linked to various diseases, including cancer and neurodegenerative disorders.
- Epigenetic mechanisms are central to homeobox gene dysregulation in lung cancer progression.

## 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.

Overview of the homeobox gene superfamily and its pathophysiological roles. The homeobox superfamily comprises several major classes, including ANTP, PRD, TALE, LIM, POU, and others. Among these, the HOX clusters (A–D) play critical roles in embryonic development specifically in conferring cellular identity, regulating morphogenesis, and guiding axial patterning. Beyond development, HOX genes remain active in adult tissue homeostasis. Dysregulation of their expression, whether through mutation or epigenetic alteration, is implicated in a broad spectrum of diseases, including multiple cancers and neurodegenerative disorders.