Table 2.
Epigenetic regulation of HOX genes in cancer
| Promoter DNA hyper methylation | |||||
| Cancer | HOX genes | Frequency | Specificity | Role | References |
| Breast cancer | HOXA4 | 46.6% | - | Biomarker for early cancer detection | Li et al. 2019b |
| Head and neck squamous cell carcinoma | HOXA9 | - | 93.8% | Promotes cancer progression and significantly correlated with lymph node metastasis | Zhou et al. 2019 |
| Epithelial ovarian cancer | HOXA9 | 82.3% | 88.6% | Potential diagnostic serum marker for early detection | Singh et al. 2020 |
| Lung cancer | HOXA9 | - | 84.2% | Biomarker for lung cancer subtyping in liquid biopsies | Nunes et al. 2019 |
| Colorectal cancer | HOXD10 | - | - | Promotes cell proliferation, migration, and invasion | Yuan et al. 2019 |
| HOXA2, HOXA5, HOXA6 | - | - | Significant association with age, stage, lymphovascular and perineural invasion | Li et al. 2019a | |
| Cholangiocarcinoma | HOXD9 | - | 90% | A potential diagnostic marker: Promotes dedifferentiation of cholangiocytes | Wasenang et al. 2019 |
| Non-coding RNAs and chromatin modification | |||||
| LncRNA-mediated HOX gene regulation | |||||
| Cancer | HOX-embedded lncRNA | Interaction with chromatin modifiers | Target, HOX genes | Role | References |
| Breast cancer, glioblastoma multiforme | HOTAIRM1↑ | EZH2 | HOXA1↑ | Promotes resistance to tamoxifen; promotes cell proliferation, migration, and invasion and suppresses apoptosis | Kim et al. 2020; Li et al. 2018 |
| Prostate cancer, pancreatic cancer, and hepatocellular carcinoma | HOTTIP↑ | WDR5 | HOXA9, HOXA13↑ | Promotes tumorigenesis | Fu et al. 2017; Malek et al. 2017; Quagliata et al. 2014 |
| Most of the cancer types | HOTAIR↑ | PRC2, LSD1 | HOXD cluster genes↓ | Promotes cell cycle progression, migration, EMT, and metastasis | Bhan and Mandal 2015 |
| Colorectal cancer | HOXD-AS1↓ | PRC2 | HOXD3↓ | Promotes proliferation, migration, and metastasis | Yang et al. 2019 |
| miRNA-mediated HOX gene regulation | |||||
| Cancer | HOX-embedded miRNA | Target, HOX genes | Downstream targets | Role | References |
| Ovarian cancer | miR-10b↑ | HOXD10↓ | MMP14, RHOC | Induces migration and invasion; contributes to the metastatic phenotype | Nakayama et al. 2013 |
| miR-196b↑ | HOXA9↓ | - | Induces cancer cell invasion and recurrence | Chong et al. 2017 | |
| Non-small cell lung cancer | miR-196a↑ | HOXA5↓ | - | Promotes cell proliferation, migration, and invasion | Liu et al. 2012 |
| Pancreatic cancer | miR-10a↑ | HOXA1↓ | - | Promotes invasive potential | Ohuchida et al. 2012 |
| miR-10a↑ | HOXB1 and HOXB3↓ | - | Promotes metastatic behavior | Weiss et al. 2009 | |
| Glioma | miR-10b↑ | HOXB3↓ | HMGB1, RHOC, and MMP2 | Promotes cell proliferation, migration, and invasion | Li et al. 2019c |
| Endometrial cancer | miR-10b↑ | HOXB3↓ | - | Promotes cell proliferation, migration, and invasion | Chen et al. 2016 |
| Clear-cell renal cell carcinoma | miR-10b↓ | HOXA3↑ | FAK, YAP | Promotes cell invasion and metastasis | He et al. 2019 |
NOTE:YAP, Yes-associated protein; FAK, focal adhesion kinase; HOTAIR-HOX, transcript antisense RNA; HOTAIRM1-HOX, antisense intergenic RNA myeloid 1; HOXD-AS1-HOXD, cluster antisense RNA 1; HOTTIP-HOXA, distal transcript antisense RNA; EZH2, enhancer of zeste 2; PRC2, polycomb repressive complex 2; WDR5-WD, repeat domain 5; LSD1, lysine-specific histone demethylase 1A; HMGB1, high mobility group box protein 1; ↑, upregulated; ↓, downregulated