Methylation in HOX Clusters and Its Applications in Cancer Therapy
Abstract
:1. Introduction
2. HOX Genes Methylation in Cancer
2.1. HOXA Genes Methylated in Cancer
2.2. HOXB and HOXC Genes Methylated in Cancer
2.3. HOXD Genes Methylated in Cancer
3. Histone Methylation with Impact on HOX Gene Transcription in Cancer
4. Therapies Targeting Methylation in HOX-Associated Cancers
5. Conclusions
6. Future Perspectives
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Cancer Site | HOX Genes | Possible Roles | References |
---|---|---|---|
Bile duct | HOXA1, HOXA2, HOXA5, HOXA11, HOXB4, HOXD9, HOXD13 | Biomarkers for the detection of cholangiocarcinoma in tissues or serum cell-free. | [31,32,33] |
Bladder | HOXA9 | Biomarker for the detection of bladder cancer and prediction response to cisplatin-based chemotherapy and survival. | [34,35] |
HOXB2 | Biomarker to predict high-grade, noninvasive disease. | [36] | |
Blood (Leukemias/ Lymphomas) | HOXA4 | Biomarker to predict resistance to imatinib mesylate. | [37] |
HOXA4, HOXA5 | Biomarkers to predict progression to blast crisis. | [38] | |
HOXD8 | Targeted for therapeutic benefit in MCL (Mantle cell lymphoma). | [39] | |
Breast | HOXA1 | Biomarker to distinguish different breast cancer states subgroups. | [24,40] |
HOXA4 | Biomarker for early breast cancer detection. | [41] | |
HOXA5 | Biomarker specific to high-grade ductal carcinoma in situ detection and Triple-Negative breast cancer nonresponders to neoadjuvant chemotherapy. | [42,43] | |
HOXA9, HOXA10 | Biomarkers to predict survival. | [44] | |
HOXA10, HOXB13 | Biomarker to distinguish different breast cancer states subgroups with high expression of estrogen and progesterone receptors. | [24,40] | |
HOXA11 | Biomarker for unfavorable prognosis in breast cancer. | [45] | |
HOXB4 | Biomarker for metastatic breast cancer detected in circulating tumor cells. | [46] | |
HOXB13 | Biomarkers for the detection of breast cancer. | [47] | |
HOXC8 | Epigenetic downregulation interferes with stem cell transformation. | [48] | |
HOXC9 | Detected in breast cancer. | [49] | |
HOXC10 | Detected in endocrine-resistant breast cancer and associated with recurrence during aromatase inhibitor treatment. | [50] | |
HOXD1 | Biomarkers for the detection and prognosis of breast cancer. | [51] | |
HOXD11 | Detected in breast cancer. | [52] | |
HOXD13 | Biomarker for poor survival prognostic. | [53] | |
Cervix | HOXA9 | Epigenetic downregulation relates to cell proliferation, migration and expression of epithelial-to-mesenchymal transition genes. | [54] |
Colorectal | HOXA2 | Epigenetic downregulation relates to lymphovascular invasion, perineural invasion, lymph node number. | [38] |
HOXA5, HOXA6 | Epigenetic downregulation favors tumor progression. | [55] | |
HOXD3 | Identified in colorectal cancers. | [56] | |
HOXD10 | Epigenetic downregulation favors proliferation, migration, invasion and apoptosis. | [57] | |
Endometrial | HOXA9, HOXD10 | Biomarker for detection of early onset of endometrial cancer. | [58] |
Kidney | HOXA5 | Epigenetic downregulation associated with high-grade clear cell renal cell carcinoma. | [59] |
HOXA11 | Epigenetic downregulation associated with proliferation, colony formation, migration and invasion abilities in renal cell carcinoma. | [60] | |
HOXB13 | Epigenetic downregulation associated with reduced apoptosis and increased tumor grade and microvessel invasion in renal cell carcinoma. | [61] | |
Head and neck | HOXA5 | Epigenetic downregulation favors invasion in nasopharyngeal cancer. | [62] |
HOXB2 | Biomarker for lymph node metastasis in esophageal squamous cell carcinoma. | [63] | |
HOXA9 | Epigenetic downregulation associated with tumor progression and metastasization in head and neck squamous cell carcinoma and biomarker to distinguish oral cancer patients at low risk of neck metastasis. | [64,65] | |
HOXB4, HOXC4 | Biomarkers to predict survival of oral squamous cell carcinoma. | [66] | |
Liver | HOXD10 | Epigenetic downregulation activates ERK signaling in hepatocellular carcinoma and causes vessel cancerous embolus and tumor cell differentiation. | [67] |
HOXB4 | Epigenetic downregulation disruption of miR-10ª regulation hepatocellular carcinoma. | [68] | |
Lung | HOXA1, HOXA11 | Biomarker involved in a molecular signature that helps to distinguish between atypical adenomatous hyperplasia, adenocarcinoma in situ and lung adenocarcinoma | [69] |
HOXA2 | Biomarker involved in a molecular signature that helps to stratify lung squamous cell carcinoma into molecular subtypes with distinct prognoses. | [70] | |
HOXA2, HOXA10 | Biomarkers relevant for the prognosis of nonsmall cell lung cancer patients. | [71] | |
HOXA3 | Epigenetic downregulation in lung adenocarcinoma is associated with progression and poor prognosis. | [72] | |
HOXA5 | Epigenetic downregulation favors tumor-node-metastasis, tumor size, and lymph node metastasis in nonsmall cell lung cancer. It also favors invasion in lung adenocarcinomas. | [73,74] | |
HOXA5, HOXA10, HOXA4, HOXA7, HOXD13 | Identified in lung cancer. | [75] | |
HOXA7, HOXA9 | Epigenetic downregulation is associated with recurrence in nonsmall cell lung cancer. This alteration is part of a molecular signature relevant for detection and prognostic of primary nonsmall cell lung cancer using serum DNA. | [76,77] | |
HOXA11 | Epigenetic downregulation is associated with progression of nonsmall cell lung cancer. This alteration is part of a molecular signature involved in cell proliferation and migration in lung adenocarcinoma. | [78,79] | |
HOXB3, HOXB4 | Biomarkers in lung adenocarcinomas correlated with smoking history and chronic obstructive pulmonary disease. | [80] | |
HOXD3 | Biomarker for lung cancer. | [56] | |
HOXD8 | Epigenetic downregulation correlated with clinicopathological characteristics, cell migration and metastasization | [81] | |
HOXD10 | Biomarker to distinguish lung cancer, pulmonary fibrosis and chronic obstructive lung disease. | [82] | |
HOXD13 | Biomarker for lung adenocarcinoma. | [83] | |
Nervous System | HOXA3, HOXA7, HOXA9, HOXA10 | Biomarkers to distinguish different glioma subgroups. | [84] |
HOXA10 | Part of a stem cell related HOX-signature in glioblastoma. | [85] | |
HOXA11 | Epigenetic downregulation associated with treatment resistance and poor prognosis in glioblastoma. | [86] | |
HOXC4, HOXD8, HOXD13 | Biomarkers that distinguish long- and short-term glioblastoma survivors. | [87] | |
Ovaries | HOXA9, HOXD11 | Epigenetic downregulation involved in DNA repair inactivation, cell cycle, apoptosis, cell adherence in ovarian cancer | [88] |
HOXA9, HOXB5 | Identified in ovarian cancer and correlated with clinicopathological characteristics. | [89] | |
HOXA10, HOXA11 | Prognostic biomarker in ovarian cancer. | [90] | |
Prostate | HOXA9 | Part of a molecular signature for prostate cancer clinical staging based on urine collection. | [91] |
HOXD3 | Identified in prostate cancer and related to the development of high-grade tumors and recurrence | [92,93] | |
HOXD8 | Urine-based methylation biomarkers to predict prostate cancer progression. | [94] | |
Stomach | HOXA1, HOXA10, HOXD10 | Biomarker for the diagnosis of gastric cancer. | [95] |
HOXA10 | Interferes with miR-196b-5p-dependent proliferation and invasion of gastric cancer cells. | [30] | |
HOXA11 | Identified in gastric cancer and proposed to affect cell proliferation. | [96] | |
HOXB13 | Biomarker for gastric cancer involved in invasion depth, lymph node metastasis and tumor-node-metastasis stage. | [97] | |
HOXD1 | Biomarkers for predicting lymph node metastasis of stomach cancer. | [98] | |
HOXD10 | Epigenetic downregulation associated with gastric carcinogenesis. | [99] | |
Testis | HOXA9 | Biomarker for testicular germ cell tumor subtyping. | [100] |
Thyroid | HOXA1 | Biomarker for the diagnosis of thyroid nodules. | [101] |
HOXA7 | Biomarker for papillary thyroid cancer. | [102] | |
HOXB4 | Part of a molecular signature identifying biologically distinct thyroid cancer subtypes. | [103] | |
HOXD10 | Identified in papillary thyroid cancer with BRAFV600E mutation and associated with primary tumor invasion and age > 45. | [104] |
Drug Candidates | Target Molecule | Effects | References |
---|---|---|---|
Zebularine | DNMTs and cytidine deaminase | Alter pan-DNA methylation status | [129] |
5-aza-deoxycytidine/5-azacytine | DNMTs | Alter pan-DNA methylation status | [128,129] |
Vorinostat/Belinostat /panobinostat/Romidepsin/Chidamide | HDACs | Alter histones methylation status | [129] |
GSK-J4 | Histones | Inhibits the histone modulator KDM6B/JMJD3 | [130] |
AC1NOD4Q | Histones | Inhibits the HOX antisense intergenic RNA (HOTAIR)/EZH2 interaction | [131] |
JQ1 | HOX antisense intergenic RNA (HOTAIR) | Inhibits the HOX antisense intergenic RNA (HOTAIR) through the BET bromodomain inhibition | [132] |
GSK-J1 | Histones | Inhibits JMJD3 and UTX demethylases | [136] |
GSK-J3 | Histones | Targeting JMJD3 demethylase | [136] |
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Paço, A.; de Bessa Garcia, S.A.; Freitas, R. Methylation in HOX Clusters and Its Applications in Cancer Therapy. Cells 2020, 9, 1613. https://doi.org/10.3390/cells9071613
Paço A, de Bessa Garcia SA, Freitas R. Methylation in HOX Clusters and Its Applications in Cancer Therapy. Cells. 2020; 9(7):1613. https://doi.org/10.3390/cells9071613
Chicago/Turabian StylePaço, Ana, Simone Aparecida de Bessa Garcia, and Renata Freitas. 2020. "Methylation in HOX Clusters and Its Applications in Cancer Therapy" Cells 9, no. 7: 1613. https://doi.org/10.3390/cells9071613
APA StylePaço, A., de Bessa Garcia, S. A., & Freitas, R. (2020). Methylation in HOX Clusters and Its Applications in Cancer Therapy. Cells, 9(7), 1613. https://doi.org/10.3390/cells9071613