Homeobox (HOX) genes encode homeodomain proteins that regulate a wide range of molecular pathways. The homeodomain is highly conserved and binds to DNA. One exception is homeodomain-only protein (HOPX) that lacks DNA-binding capacity. HOPX plays a crucial role in development and its functional impairment is associated with a variety of diseases, including cancer. Loss of HOPX function occurs in a wide range of cancer types, where it functions as a tumor suppressor gene. Understanding the molecular mechanisms by which HOPX regulates carcinogenesis will likely lead to the development of new therapeutic approaches.

Homeobox genes are master regulators of morphogenesis and differentiation by acting at the top of genetic hierarchies and their deregulation is associated with a variety of human diseases. They usually contain a highly conserved sequence that codes for the homeodomain of the protein, a specialized motif with three α helices and an N-terminal arm that aids in DNA binding. However, one homeodomain protein, HOPX, is unique among its family members in that it lacks the capacity to bind DNA and instead functions by interacting with transcriptional regulators. HOPX plays crucial roles in organogenesis and is expressed in both embryonic and adult stem cells. Loss of HOPX expression is common in cancer, where it functions primarily as a tumor suppressor gene. In this review, we describe the function of HOPX in development and discuss its role in carcinogenesis.