In vertebrates, the genes encoding the class of transcription factors called homeobox genes are found in clusters named A, B, C, and D on four separate chromosomes. Expression of these proteins is spatially and temporally regulated during embryonic development. This gene is part of the A cluster on chromosome 7 and encodes a DNA-binding transcription factor which may regulate gene expression, morphogenesis, and differentiation. Methylation of this gene may result in the loss of its expression and, since the encoded protein upregulates the tumor suppressor p53, this protein may play an important role in tumorigenesis.[3]
HoxA5 is controlled, at least in part, by DNA methylation.[4] HoxA5 has been shown to upregulate the tumor suppressor p53 and AKT1 by downregulation of PTEN.[5] Suppression of HoxA5 has been shown to attenuate hemangioma growth.[6] HoxA5 has far-reaching effects on gene expression, causing ~300 genes to become upregulated upon its induction in breast cancer cell lines.[7] HoxA5 protein transduction domain overexpression prevents inflammation shown by inhibition of TNFα-inducible monocyte binding to HUVECs.[8][9]
Comparison of the HoxA5 promoter methylation profile across cell types from the least differentiated (human embryonic stem cells) to the most endothelial-like (human umbilical vein endothelial cells, or HUVECs) shows that the HoxA5 promoter is normally heavily methylated in non-differentiated cells and becomes demethylated as cells differentiate down the endothelial lineage.[10] HoxA5 contains a C-Amp Response Elements (CRE) in its promoter.[4] POL2 and CTCF binding are enriched at the CpG-dense HoxA5 promoter in HUVECs, demonstrating transcriptional activity.[10]
Clinical significance
HoxA5 is suppressed in acute myeloid leukemia (AML), and the DNMT inhibitor decitabine (5Aza) is used to treat this disease. While HoxA5 is known to be hypermethylated in AML, it has not yet been shown whether decitabine directly targets these genes for demethylation.[11][12]
↑Chen H, Rubin E, Zhang H, Chung S, Jie CC, Garrett E, Biswal S, Sukumar S (May 2005). "Identification of transcriptional targets of HOXA5". The Journal of Biological Chemistry. 280 (19): 19373–80. doi:10.1074/jbc.M413528200. PMID15757903.
↑Lee JY, Park KS, Cho EJ, Joo HK, Lee SK, Lee SD, Park JB, Chang SJ, Jeon BH (Jul 2011). "Human HOXA5 homeodomain enhances protein transduction and its application to vascular inflammation". Biochemical and Biophysical Research Communications. 410 (2): 312–6. doi:10.1016/j.bbrc.2011.05.139. PMID21664342.
↑Strathdee G, Sim A, Soutar R, Holyoake TL, Brown R (Feb 2007). "HOXA5 is targeted by cell-type-specific CpG island methylation in normal cells and during the development of acute myeloid leukaemia". Carcinogenesis. 28 (2): 299–309. doi:10.1093/carcin/bgl133. PMID16861263.
↑Kim SY, Hwang SH, Song EJ, Shin HJ, Jung JS, Lee EY (Oct 2010). "Level of HOXA5 hypermethylation in acute myeloid leukemia is associated with short-term outcome". The Korean Journal of Laboratory Medicine. 30 (5): 469–73. doi:10.3343/kjlm.2010.30.5.469. PMID20890077.
1hom: DETERMINATION OF THE THREE-DIMENSIONAL STRUCTURE OF THE ANTENNAPEDIA HOMEODOMAIN FROM DROSOPHILA IN SOLUTION BY 1H NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY
1san: THE DES(1-6)ANTENNAPEDIA HOMEODOMAIN: COMPARISON OF THE NMR SOLUTION STRUCTURE AND THE DNA BINDING AFFINITY WITH THE INTACT ANTENNAPEDIA HOMEODOMAIN
