Abstract
Stem cells are undifferentiated cells that have the unique ability to self-renew and differentiate into many different cell types. Their function is controlled by core gene networks whose misregulation can result in aberrant stem cell function and defects of regeneration or neoplasia. HOX genes are master regulators of cell identity and cell fate during embryonic development. They play a crucial role in embryonic stem cell differentiation into specific lineages and their expression is maintained in adult stem cells along differentiation hierarchies. Aberrant HOX gene expression is found in several cancers where they can function as either oncogenes by sustaining cell proliferation or tumor-suppressor genes by controlling cell differentiation. Emerging evidence shows that abnormal expression of HOX genes is involved in the transformation of adult stem cells into cancer stem cells. Cancer stem cells have been identified in most malignancies and proved to be responsible for cancer initiation, recurrence, and metastasis. In this review, we consider the role of HOX genes in normal and cancer stem cells and discuss how the modulation of HOX gene function could lead to the development of novel therapeutic strategies that target cancer stem cells to halt tumor initiation, progression, and resistance to treatment.
Highlights
SVMS, Faculty of Medicine and Health Sciences, University of Nottingham, Sutton Bonington Campus, Nottingham Breast Cancer Research Centre and Centre for Cancer Sciences, University of Nottingham, Centre for Biomolecular Sciences, Nottingham NG7 2RD, UK
HOX genes are not expressed before gastrulation, and they are not transcribed in embryonic stem cells (ESC) derived from the inner cell mass of a blastocyst [26]
By screening homeobox gene expression in breast cancer stem cells (CSC), we demonstrated that epigenetic silencing of HOXC8 mediated by MIR-196 and DNA methylation induces a CSC phenotype in normal mammary stem cells, and it results in their increased self-renewal, impaired differentiation, and augmented tumorigenic potential [70]
Summary
HOX genes encode evolutionarily conserved transcription factors that are expressed under temporal and spatial control to establish patterning and morphogenesis in the vertebrate embryo. As a result of their epigenetic regulation, HOX-coded transcription factors can act as either transcriptional activators or repressors of target genes These consist of factors that regulate diverse biological processes and include a network of transcription factors, signaling molecules, components of signaling pathways, and “realizator” genes that are directly involved in cell differentiation and tissue organization [16,17]. These include the PBC and MEINOX classes of transcription factors, with the PBC family comprising PBX proteins (PBX1-4) and the MEINOX family including MEIS (MEIS1-3) and PREP (PRE1-2) proteins All of these transcription factors cooperate with HOX proteins by forming heteromeric complexes, [18,19] and their diverse and context-dependent interaction regulates cell fate decisions and specific cell functions during embryo patterning and morphogenesis
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