Bilaterian animals operate the clusters of Hox genes through a rich repertoire of diverse mechanisms, including, due to a large set of various non-coding RNAs. Long non-coding RNAs (lncRNAs), which are transcribed from the sense (coding) DNA strands of Hox clusters, control the work of Hox genes in the cis and trans position, are involved in the establishment and maintenance of the epigenetic code of Hox loci, and can even serve as a source of regulatory peptides. which switch cellular energy metabolism. All antisense lncRNAs in human Hox clusters are therapeutic targets for malignant tumors, and their careful study has profound practical meaning.
LncRNA | Length (nt) | Type of LncRNA | Position in the Hox Cluster | ||||||||
---|---|---|---|---|---|---|---|---|---|---|---|
Targets | Orthologs | Discovered in | Refs | ||||||||
HOXA Cluster | |||||||||||
HOTAIRM1 | Control of the cell cycle in the myeloid cell lineage; control of the differentiation of granulocytes; control of neuronal differentiation timing; control of osteogenesis in dental follicle stem cells | Serve as protein scaffolds; Enhancer; Sponges big set miRNAs |
Nucleus Cytoplasm | HOXA cluster; NEUROGENIN 2; miR-196b; miR-125b | Chordata | 2009 | [36][39][40][41][42][43][44] | HOTAIRM1 | 4000; 1052; 783 | Linc | |
HOXA-AS2 | Promotion of proliferation, migration and invasion in many types of tumors; regulation EMT; negative regulates endothelium inflammation | Serve as protein scaffolds; HOXA1→HOXA2 |
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Sponges big set miRNAs | Nucleus | Cytoplasm |
c-MYC; EGFR; Bax/TRAIL; EZH2/LSD1; PBX3; NF-kB; miR-373 | Primates | 2013 | [45][46][47][48][49] | HOXA-AS2 | 1048 | Linc or NAT | HOXA3→H | |
HOXA-AS3 | OXA4 | ||||||||||
Control of cell cycle, proliferation, migration and apoptosis in many types of cancer cells; positive regulation of endothelium inflammation; activation the MEK/ERK Signaling Pathway | Stabilization of HOXA6 mRNA, sponges miR-29c and mir-455-5p | Nucleus Cytoplasm |
HOXA6; NF-kB; miR-29c | Homo sapiens | 2017 | [50][51][52][53][54] | HOXA-AS3 | 3918; 3992 | Linc or NAT | HOXA4→A5,→A6→HOXA7 | |
HOXA10-AS | |||||||||||
HOXA10-AS | 1161 | Linc or NAT | HOXA9→HOXA10 | ||||||||
Cell cycle and apoptosis control in glioma, lung adenocarcinoma (LAD), oral cancer and acute myeloid leukemia (AML) cells | ? | Cytoplasm | HOXA10; Wnt pathway; NF-kB |
Birds Mammals |
2018 | [55][56][57][58] | |||||
HOXA11-AS | Control of the menstrual cycle; cell cycle, proliferation, migration and apoptosis control in many types of cancer cells | Serve as protein scaffolds; Sponges big set miRNAs |
Nucleus Cytoplasm |
HOXA11; TGF-b pathway, LATS1; CyclinD1; CyclinE; CDK4; CDK2 | Rodents Primates Bamboo shark |
2002 | [59] | HOXA11-AS | 1628 | Linc or NAT | HOXA11→HOXA13 |
HOTTIP | Control of 5′HOXA genes’ transcription during development. Participation in pathogenesis of almost all types of cancer. | Activates HOXA genes through recruiting of WDR5 и MLL | Nucleus | HOXA7-HOXA13; LSD1; EZH2; IL-6; miR-30b | Rodents Primates Bamboo shark |
2011 | [60][61] | HOTTIP | 4665 | Linc or NAT | HOXA13→EVX1 |
HOXB-AS1 | Glioblastoma and endometrial carcinoma and multiple myeloma (MM) promotion | ILF3-mediated activation of HOXB3 and HOXB3 transcription; stabilization of their mRNAs; stabilization of FUT4 mRNA | Nucleus Cytoplasm |
HOXB2; HOXB3; Wnt pathway; FUT4; miR-186-5p; miR-149-3p | Homo sapiens | 2019 | [62][63][64] | HOXB Cluster | |||
HOXB-AS2 | Potentially participate in the development of atrial fibrillation | ? | ? | ? | Homo sapiens | 2020 | [65] | HOXB-AS1 | 797 | Linc or NAT | HOXB2→H |
HOXB-AS3 | OXB3 | ||||||||||
Control of energetic metabolism in the cell through alternating the isoforms of pyruvate kinase M (PKM); promoting of the cancer processes through repression of p53 transcription; activation of PI3/AKT pathway | Codes the conservative peptide of 53 amino acids long, which is important for PKM splicing; Sponges miRNAs | Nucleus Cytoplasm |
PKM; DNMT1; p53; I3K-AKT-mTOR pathway; miR-378a-3p |
Homo sapiens Rodents |
2017 | [66][67][68][69][70] | HOXB-AS2 | 3594 | NAT RNA | HO | |
HOXB-AS4 | XB3 | ||||||||||
The sequence is differentially methylated in normal and pancreatic cancer cells | ? | ? | ? | Homo sapiens | 2018 | [71] | HOXB-AS3 | 785; 611; 549; 545; 514; 452; 446; 336 | Linc or NAT * | HOXB4→B5→HOXB6 | |
HOXB-AS5 or PRAC2 |
Associated with breast cancer (lncRNA) and protstate cancer (protein) | Encodes 140 aa nuclear protein |
Nucleus (protein) | I3K-AKT-mTOR pathway (lncRNA) | Artiodactyla Bats Colugo Primates |
2003 (protein) 2017 (lncRNA) |
[72][73 | HOXB-AS4 | 543; 513 | Linc | HOXB9→HOXA13 |
] | |||||||||||
HOXC-AS1 | Cholesterol homeostasis participation, inhibition of atherosclerosis; promotion of growth and metastatic formation in several types of malignant tumors | Promotes the transcription and translation of HOXC6; boosts c-MYC mRNA | Nucleus Cytoplasm |
HOXC6; miR-590-3p; c-MYC; Wnt pathway; miR-590-3p |
Homo sapiens | 2016 | [74][75][76][77][78] | PRAC2 | 1193; 560; 518; 503; 448 | Linc * | HOXB9→HOXA13 |
HOXC-AS2 | Promotion of growth and metastatic formation in several types of malignant tumors | Promote HOXC13 transcription; can sponge miR-876-5p to affect ZEB1 expression | Nucleus Cytoplasm |
HOXC13; ZEB1; miR-876-5p |
Homo sapiens | 2019 | [79][80][81][82] | HOXC Cluster | |||
HOXC-AS3 | Functions under the direct control of HOXB1. Promotion of growth and metastatic formation in several types of malignant tumors |
Promote the transcription of 5’HOXC genes; stabilizes HOXC10 mRNA; can sponge miR-3922-5p, impairs the maturation of miR-96 | Nucleus | HOXC8; HOXC9; HOXC10; HOXC11; HOXC12; HOXC13; YBX1; thymidine kinase 1 (TK1); FOXM1; miR-96; miR-3922-5p | Homo sapiens | 2018 | [37][81][82][83][84][85][86][87][88][89] | HOXC-AS1 | 548 | ||
HOTAIR | Reprogramming of chromatin state to promote cancer metastasis; PRC2 and PRC2-independent induction of transcriptional repression. Promotion of growth and metastatic formation in several types of malignant tumorsIntronic | Scaffold: A 5′ domain of HOTAIR binds PRC2, whereas a 3′ domain of HOTAIR binds the LSD1/CoREST/REST complex; HOXC9 |
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Sponging big set microRNA | Nucleus | Cytoplasm |
HOXD cluster (40 Kb in 5′area) HOXA1; HOXA5; HOXC11; p53; p27; E-cadherin; NOTCH1/JAGGED1; SNAIL; GLI2; Protocadherin 10; Wnt pathway; Dozens of miRNAs, critical for proliferation and differentiation control | Rodents Carnivores Primates Marsupials |
2007 | [28][35][90][91][92][93][94][95][96][97][98][99][100][101][102][103][104][105][106][107][108][109][110][111][112][113][114][115][116][117][118][119] | HOXC-AS2 | 504 | Linc or NAT | HOXC9→H | |
HOXC13-AS | OXC10 | ||||||||||
Promotion of proliferation, migration and invasion of cells of several cancer types | Sponging big set microRNA | Cytoplasm | HOXC13; c-MYC; miR-383-3p; miR-497-5p |
Homo sapiens | 2019 | [120][121][122][123][124] | HOXC-AS3 | 368 | Linc or NAT | HOXC10→HOXC11 | |
HAGLR or HOXD-AS1 | Impairment of HAGLR regulation (up or down) to promote growth and metastatic formation of several types of malignant tumors | Binds to WDR5 and EZH2 for activation and repression of target genes | Nucleus | HOTAIR | 2370; 2364; 2337 | Linc | HOXC11→HOXC12 | ||||
HOXC13-AS | 1408 | Linc or NAT | HOXC9→ | ||||||||
HOXD Cluster | |||||||||||
HAGLR | 4086; 4037; 4007; 3942; 3923; 3905; 3893; 3891; 3821; 3812; 3794; 3782 | Linc or NAT | HOXD1→HOXD3 | ||||||||
HOXD-AS2 | 692 | Linc or NAT | HOXD4→D8→D9→HOXD10 |
As ncRNA | Functions | Mechanism of Work | Localization | ||||
---|---|---|---|---|---|---|---|
Cytoplasm | |||||||
HOXD3; | |||||||
JAK2/STAT3 pathway; Wnt pathway; Ras/ERK pathway; TGF-β pathway; p57; miR-133a-3p; miR-133b; miR-130a; miR-185-5p | |||||||
Rodents | |||||||
Primates | |||||||
2014 | |||||||
[ | |||||||
125 | |||||||
] | |||||||
[ | 126 | ] | [ | 127 | ] | [ | 128][129][130][131][132][133][134][135][136][137][138] |
HOXD-AS2 | Downregulation of HOXD-AS2 significantly promotes the progression of gastric cancer | ? | Cytoplasm | HOXD8; PI3K/Akt pathway |
Homo sapiens | 2018 | [139][140][141][142][143][144][145][146][147][148][149] |
ineages - Deuterostomia, Lophotrochozoa, and Ecdysozoa. Individual human lncRNAs are listed in Tab1.