Contingent Synergistic Interactions between Non-Coding RNAs and DNA-Modifying Enzymes in Myelodysplastic Syndromes
Abstract
:1. Introduction
2. The Course of Aberrant DNA Methylation Patterns in MDS
3. Long Non-Coding RNAs and MicroRNA Species’ Involvement in MDS
4. Non-Coding RNA Species Cooperate with DNA Modifying Enzymes
5. Conclusions and Future Perspectives
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Conflicts of Interest
Abbreviations
5hmC | 5-hydroxy-methylcytocine |
5mC | 5-methylcytocine |
AGO | Argonaute |
AML | Acute Myeloid Leukemia |
AZA | Azacytidine |
BC | Breast cancer |
BCL-2 | B-cell lymphoma 2 (protein) |
BENC1 | Beclin-1 protein encoding gene |
BMMC | bone marrow mononuclear cells |
CASP8 | Caspase-8 |
CDC2 | Cyclin-dependent kinase 2 |
CDK6 | Cyclin Dependent Kinase 6 |
CDKN1B | Cyclin-Dependent Kinase Inhibitor 1B |
CDKN2A | Cyclin-Dependent Kinase 2A |
CEBPA | CCAAT/Enhancer-Binding Protein Alpha |
CpG | cytosine nucleotide followed by a guanine nucleotide |
CRC | Colorectal cancer |
DAC | Decitabine |
DACOR1 | DNMT1-associated Colon Cancer Repressed 1 |
DANCR-lncRNA | Differentiation antagonizing nonprotein coding RNA |
DCs | dendritic cells |
DICER | endoribonuclease Dicer or helicase with RNase motif |
DNA | Deoxyribonucleic acid |
DNMT | DNA methyltransferase |
DROSHA | Drosha Ribonuclease III |
DsDNA | double stranded Deoxyribonucleic Acid |
DSB | DNA double strand breaks |
E2F1 | E2F Transcription Factor 1 |
EZH2 | Enhancer Of Zeste 2 Polycomb Repressive Complex 2 Subunit |
FoxO | Forkhead box O |
GB | Glioblastoma |
H19 | H19 Imprinted Maternally Expressed Transcript |
H3K9me | methylated histone H3 at lysine 9 |
HCC | hepatocellular carcinoma |
HDAC | Histone deacetylase |
HIF-1 | Hypoxia-inducible factor 1 |
HMAs | Hypomethylating agents |
HOAX1 | Homeobox A1- protein coding gene |
HOAX5 | Homeobox A5 |
HOTAIR | Homeobox (HOX) transcript antisense RNA |
HOTAIRM1 | HOXA Transcript Antisense RNA, Myeloid-Specific 1 |
HOTTIP | HOXA Distal Transcript Antisense RNA |
HOXB-AS3 | HOXB Cluster Antisense RNA 3 |
HR | homologous recombination |
HR-MDS | high-risk Myelodysplastic Syndromes |
HSC | hematopoietic stem cell |
IDH | Isocitrate dehydrogenase |
IL-6 | Interleukin-6 |
IPSS | International prognostic scoring system |
IPSS-R | Revised international prognostic scoring system |
jak-STAT | The Janus kinase—signal transducer and activator of transcription pathway |
LEF1-AS1 | Lymphoid enhancer-binding factor 1 (LEF1) antisense RNA 1 |
LncRNAs | long non-coding RNAs |
LRIG1 | Leucine Rich Repeats And Immunoglobulin Like Domains 1 |
LSCC | laryngeal squamous cell carcinoma |
MDM2 | E3 Ubiquitin Protein Ligase |
MAGI2-AS3 | MAGI2 Antisense RNA 3 |
MALAT1 | Metastasis-Related Lung Adenocarcinoma Transcript 1 |
MAPK | Mitogen-Activated Protein Kinase |
MBD-domain | Methyl-CpG-binding domain |
MDS | Myelodysplastic syndromes |
MEG3 | Maternally Expressed 3 |
miRNAs | microRNAs |
MM | multiple myeloma |
Nanog | Nanog Homeobox |
NcRNAs | non-coding RNAs |
NEAT1 | Nuclear Paraspeckle Assembly Transcript 1 |
Nt | Nucleotide |
NPM1 | Nucleiphosmin-1 |
Oct3 | Octamer binding transcription factor 3 |
ORF | open reading frame |
PC | prostate cancer |
PKCd | protein kinase C delta |
PI3K-Akt | Phosphatidyl-Inositol-3-Kinase- |
PiRNAs | Piwi-interacting RNAs |
Pol II | RNA polymerase II |
PRKDC | Protein Kinase DNA-Activated Catalytic Subunit |
PTEN | Phosphatase and tensin homolog |
PWWP domain | ‘Pro-Trp-Trp-Pro’ core amino acid sequence |
RNA | Ribonucleic Acid |
RITS | RNA-induced transcriptional silencing |
ROS | reactive oxygen species |
SAM | S-adenosyl methionine |
SCLC | Small cell lung carcinoma |
SiRNAs | small interfering RNAs |
SLE | Systemic Lupus Erythematosus |
SnoRNP | Small nucleolar ribonucleoprotein |
TET | Ten-Eleven Translocation or methyl-cytosine dioxygenase |
TGFβ | Transforming Growth Factor-β |
Th17 | T helper 17 cells (Th17)—a subset of pro-inflammatory T helper cells defined by their production of interleukin 17 (IL-17) |
UCA1 | Urothelial Cancer Associated 1 |
XIST | X-inactive specific transcript |
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Upregulated miRNAs | Tissue | Impaired KEGG Pathways | Gene Targets within KEGG Pathway |
---|---|---|---|
miR-196b-5p | Bone marrow | PI3K-Akt/TGFβ signaling | BRAF, TGFBR1, E2F2, NRAS, AF1, CDKN1B, SMAD4, MYC, MAPK1, MDM2 |
ECM-receptor interaction | ITGB1, ITGB8, THBS2, ITGA3, COL3A1, COL1A2, HMMR | ||
cell cycle via MAPK signaling | ESPL1, CCNB1, E2F2, CDK2, CND2, SMC3, CDKN1B, STAG1, YWHAB, SMAD4, SKP2, MYC, PLK1, MDM2, MCM3 | ||
miR-320c, miR-320d | Bone marrow | TGFβ signaling | PPP2CA, SMAD3, ACVR2B, SMAD7, MAPK1 |
miR-422a | Bone marrow | GNG12, MAPK1, GNG5, YAP1 | |
miR-617 | Bone marrow | RNA transport, translation initiation | XPO1, EIF5, EIF5B, EIF4G2 |
miR-181a, further divided to miR-181a-2-3p, miR-181a-3p and miR-181a-5p | Bone marrow | Signaling pathways regulating pluripotency of stem cells | IGF1R, HESX1, WNT8A, POU5F1B, ACVR2B, JAK3 |
miR-222, further dived to miR-222-3p and miR-222-5p | Bone marrow | PI3K-Akt/TGFβ signaling | SOS2, CDK4, E2F2, CRKL, RUNX1, CDKN1B, CDK6, E2F3, MYC, MAPK1, MDM2 |
cell cycle via MAPK signaling | YWHAH, CDK4, E2F2, YWHAE, YWHAG, CDKN1B, WEE1, CDK1, CDK6, ATM, CDKN1C, E2F3, MYC, YWHAZ, CDC20, BUB1B, CDC27, PRKDC, MDM2, CDC25A | ||
miR-210, further divided to miR-210-3p and miR-210-5p | Bone marrow | No related pathway | |
let-7a, further divided to let-7a-2-3p, let-7a-3p and let-7a-5p | Bone marrow | cell cycle via MAPK signaling | 46 genes targeted/CREBBP, CDK6, WEE1, MAP3K1, ELK4, MAX and TAOK1 confirmed by more than 1 lists |
FoxO, HIF-1 and PI3K-Akt signaling | Over than 100 genes targeted/IRS2, CREBBP, BCL2L11, SLC2A1, TFRC, EFNA1, PRKAA1, COL4A1 and CDK6 confirmed by more than 1 lists | ||
miRNA-34a (further dived to miRNA-34a-3p and -5p) in del(5q) MDS | PI3K-Akt/TGFβ signaling | 35 genes targeted | |
cell cycle via MAPK signaling | Over than 100 genes targeted/PRKDC, DUSP16 and MCM7 confirmed by more than 1 lists | ||
Cell cycle and apoptosis via P53 signaling | 34 genes targeted/THBS1, confirmed by more than 1 lists | ||
miRNA-125b-1-3p in translocation (p21;q23) MDS | Plasma/bone marrow | No related pathway | |
miRNA-383 (further divided to miR-383-3p and -5p) in trisomy 8 MDS | Bone marrow | No related pathway | |
downregulated miRNAs | |||
miR-29b further divided to miR-29b-1-5, -2-5p and -3p | Bone marrow | PI3K-Akt/TGFβ signaling | 63 genes targeted/PKN2, SGK1, NRAS, CCND1, YWHAB, CDK6, MCL1 and MDM2 confirmed by more than 1 lists |
cell cycle via MAPK signaling | 33 genes targeted/MDM2, SMC1A, YWHAB, CCND1, CDK6, HDAC1 and WEE1 confirmed by more than 1 lists | ||
Cell cycle and apoptosis via P53 signaling | 22 genes targeted/CCND1, CDK6 and MDM2 confirmed by more than 1 lists | ||
FoxO signaling | 27 genes targeted/GF1R, NRAS, STK4, SGK1, MDM2, CCND1 and GABARAP confirmed by more than 1 lists | ||
miR-130b-5p | Plasma | Cell cycle and apoptosis via P53 signaling | ZMAT3, CDK6, CHEK1, ATM, CCND1, MDM4, RRM2, SESN3, SERPINE1, PPM1D, MDM2 |
miR-30e further divided to miR-30e-3p and -5p | Bone marrow | Cell cycle and apoptosis via TGFβ signaling | FST, TGFBR1,SMAD2, THBS1, CUL1, INHBA, DCN,MYC, PPP2R1A, SMURF1, ZFYVE9, BMP2, SP1, EP300, SMAD7, E2F4, MAPK1, PPP2R1B, TGFBR2, BMPR2, RPS6KB1, the underlined confirmed by more than 1 lists |
cell cycle via MAPK signaling | 39 genes targeted/MDM2, SMAD2, YWHAZ, PRKDC, STAG2, MYC, CDK6, CCNB1 and E2F3 confirmed by more than 1 lists | ||
Cell cycle and apoptosis via P53 signaling | 24 genes targeted/MDM2, CDK6, CCNB1, CCNG1, CASP3 and SIAH1 confirmed by more than 1 lists | ||
RNA transport, translation initiation | 37 genes targeted/XPO1, NCBP1 and RANBP2 confirmed by more than 1 lists | ||
miR-221 further divided to miR-221-3p and -5p | Plasma | mRNA surveillance pathway | 21 genes targeted/ACIN1 and PABPC1 confirmed by more than 1 lists |
cell cycle via MAPK signaling | 26 genes targeted/CCND1 confirmed by more than 1 lists | ||
Cell cycle and apoptosis via P53 signaling | 50 genes targeted/EFNA1, CDKN1B, CCND1 and ATF4 confirmed by more than 1 lists | ||
miRNA-194-5p | Bone marrow | Ubiquitin mediated proteolysis | WWP1, TRIP12, CBLB, BIRC6, SMURF1, DDB1, CDC23, RBX1, UBE2W, UBE2B, PIAS1, CUL4B |
miRNA-146a (further dived to miRNA-146a-3p and -5p) in del(5q) MDS | Peripheral blood mononuclear cells | cell cycle via MAPK signaling | GSK3B, CCNB1, CDC25B, YWHAG, CDKN1B, SMAD4, RBL1, CDC23, CDKN1A, PRKDC, MDM2, ABL1, CDC25A |
miRNA-125b-1 | No related pathway |
Non-Coding RNA | Epigenetic Enzyme Targeted | Disease/Tissue of Investigation | Gene/Function Implicated | Possible Relation in MDS/AML Pathogenesis |
---|---|---|---|---|
MAGI2-AS3-lncRNA | ↑TET2 | AML | ↑LRIG1 [89] | - |
HOTAIR-lncRNA | ↑DNMT3B ↑EZH2, DNMT1/3B | AML SCLC | ↓PTEN [77], ↓HOXA5 [78] ↓HOAX1 [76] | - |
HOXB-AS3-lncRNA | ↕EZH2 | Liver cancer | ↑DICER1 [83] | Implicated in myeloid cell proliferation with adverse prognosis in AML and MDS [15] |
H19-lncRNA | ↨DNMT3B | BC | ↑BECN1/ autophagy [87] | Associated with adverse prognosis in MDS patients [86] BECN1 is also implicated in MDS autophagy [88] |
HOTAIRM1-lncRNA | ↨EZH2/DNMTs | GB | ↑HOAX1 [82] | Associated with leukemia cell autophagy and proliferation and adverse prognosis in NPM1-mutated AML [80,81] |
NR-104098-lncRNA | ↓EZH2 (via E2F1) | AML | Inhibits AML proliferation & Induces differentiation [84] | - |
CEBPA-lncRNA | ↨DNMT1 | AML | ↑CEBPA [71,72] | - |
DACOR1-lncRNA | ↨DNMT1 | CRC | Whole genome demethylation [74] | MDS have abnormal methylation patterns across many genomic regions [4,5,6,7] |
miR-22 | ↓TET2 | HSC | provoke MDS in mice [106] | Significant prognostic value in MDS treated with HMAs [105] |
Let-7 family | ↓TET2 | murine macrophages | ↑ IL-6 [107] | Altered methylation and expression profiles in MDS [10,11] |
miR-101 | ↓EZH2 | LSCC | ↓autophagy, proliferation & ↑apoptosis [110] | Reduces incidence and delays the onset and progression of AML in mice [108] |
miR-124 | ↓EZH2 | MM | ↓CDKN2A ↓proliferation &viability of myeloma cell line [111] | Potential marker of response to DAC in MDS/AML [109] |
miR-21 | ↓EZH2 ↓DNMT1 | Lung cancer SLE | ↓Cdc2, cyclinB1, BLC-2 [94] aberrant DNA hypomethylation [92] | Potential biomarker of epigenetic therapy in MDS [93] |
miR-29b | ↓DNTM3A/B, ↓DNMT1 | AML | global DNA hypomethylation [96] | - |
miR-29a | ↓DNTM3A/B | Lung cancer | Re-expression of methylation-silenced tumor suppressor genes [97] | Downregulated in AML [98] |
miR-221 | ↓DNTM3B | BC | ↓ methylation levels of Nanog & Oct 3 [103] | Decreased levels in AML evolving from MDS [104] |
miR-185 | ↓DNMT1 | HCC | ↑PTEN/Akt pathway | PTEN is associated with HMA resistance in MDS and progression to AML [79] |
miR-152 | ↓DNMT1 | PC | ↑PTEN | PTEN is associated with HMA resistance in MDS and progression to AML [79] |
miR-148a | ↓DNMT1 | SLE AML | aberrant DNA hypomethylation [92] ↑miR-148a, mutual negative feedback loop/↓cell proliferation & ↑ apoptosis [95] | - |
miR-34b | ↓DNMT1, HDAC1, HDAC2 & HDAC4 | PC | ↓proliferation through demethylation/active chromatin modifications/Akt pathway [112] | Cell viability inhibition/enhance cell apoptosis in AML cell lines [113] |
miR-342 | ↓DNMT1 | CRC | ↓ cancer cell proliferation & invasion | Downregulation in AML [102] |
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Symeonidis, A.; Chatzilygeroudi, T.; Chondrou, V.; Sgourou, A. Contingent Synergistic Interactions between Non-Coding RNAs and DNA-Modifying Enzymes in Myelodysplastic Syndromes. Int. J. Mol. Sci. 2022, 23, 16069. https://doi.org/10.3390/ijms232416069
Symeonidis A, Chatzilygeroudi T, Chondrou V, Sgourou A. Contingent Synergistic Interactions between Non-Coding RNAs and DNA-Modifying Enzymes in Myelodysplastic Syndromes. International Journal of Molecular Sciences. 2022; 23(24):16069. https://doi.org/10.3390/ijms232416069
Chicago/Turabian StyleSymeonidis, Argiris, Theodora Chatzilygeroudi, Vasiliki Chondrou, and Argyro Sgourou. 2022. "Contingent Synergistic Interactions between Non-Coding RNAs and DNA-Modifying Enzymes in Myelodysplastic Syndromes" International Journal of Molecular Sciences 23, no. 24: 16069. https://doi.org/10.3390/ijms232416069