Abstract
HOX genes are commonly known for their role in embryonic development, defining the positional identity of most structures along the anterior–posterior axis. In postembryonic life, HOX gene aberrant expression can affect several processes involved in tumorigenesis such as proliferation, apoptosis, migration and invasion. Epigenetic modifications are implicated in gene expression deregulation, and it is accepted that methylation events affecting HOX gene expression play crucial roles in tumorigenesis. In fact, specific methylation profiles in the HOX gene sequence or in HOX-associated histones are recognized as potential biomarkers in several cancers, helping in the prediction of disease outcomes and adding information for decisions regarding the patient’s treatment. The methylation of some HOX genes can be associated with chemotherapy resistance, and its identification may suggest the use of other treatment options. The use of epigenetic drugs affecting generalized or specific DNA methylation profiles, an approach that now deserves much attention, seems likely to be a promising weapon in cancer therapy in the near future. In this review, we summarize these topics, focusing particularly on how the regulation of epigenetic processes may be used in cancer therapy.
Highlights
The development of cancer is tightly linked to an accumulation of changes in the structure and function of the genome that result in transcriptional regulation errors and altered gene expression [1]
In lung adenocarcinoma, HOXA11 hypermethylation seems to be related to cisplatin-resistance and to Akt/β-catenin signaling activation, which occurs without interfering with the methylation status of HOXA11 antisense (HOXA11AS) [112]
There are HOXC genes that are hypomethylated in cancer; this is the case of HOXC10 in gastric cancer, which is associated with cell proliferation and migration [29]
Summary
The development of cancer is tightly linked to an accumulation of changes in the structure and function of the genome that result in transcriptional regulation errors and altered gene expression [1]. A wide variety of enzymes participate in these processes such as acetyltransferases, deacetylases, methyltransferases, demethylases and kinases All these enzymes work in concert with ATP-dependent chromatin-remodeling complexes that recognize specific histone modifications, affecting the disassembly and assembly of nucleosomes and the movement of histone octamers along the DNA [10]. A large number of studies, including genome-wide association approaches, have highlighted connections between HOX gene expression and cancer, either being downregulated or upregulated in comparison with its normal counterparts, where they may act as tumor suppressors or proto-oncogenes in a tissue-specific context [17] These alterations in HOX gene expression could be the result of epigenetic processes that affect chromatin accessibility, or genetic processes that affect the HOX gene. We report the histone methylation processes shown to have an impact on HOX gene transcription associated with cancer, and we discuss the therapies targeting methylation in HOX-associated cancers
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