The Intricate Interplay between Epigenetic Events, Alternative Splicing and Noncoding RNA Deregulation in Colorectal Cancer
Abstract
:1. Introduction
2. Epigenetic Modulators, Modifiers and Mediators in CRC
3. The Interplay between Non-Coding RNAs and Epigenetics in CRC
3.1. Noncoding RNAs and DNA Methylation in CRC
3.2. Noncoding RNAs, Chromatin Remodeling, and Histone Modifications in CRC
4. Regulation of Alternative Splicing in CRC
4.1. Epigenetic Regulators of Alternative Splicing in CRC
4.1.1. Modulation of RNA Pol II Elongation Rate
4.1.2. Splicing Factor Recruitment or Sequestration
4.2. Non-Coding RNAs and the Regulation of Alternative Splicing in CRC
5. Epi-Biomarkers and Promising Targets for the Design of epi-Drugs
6. Future Directions
Supplementary Materials
Funding
Conflicts of Interest
References
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Non-Coding RNAs | Epigenetic Partner/Other Epigenetic Mediator | Target Gene | Tumorigenic Effects | Reference |
---|---|---|---|---|
LncRNA & DNA methylation | ||||
DACOR1 | interaction with DNMT1 to reprogram genome-wide DNA methylation | DNA methylation at thousands of CpG sites | increased clonogenicity | [49,50] |
HIF1A-AS2 | regulates miR-129-5p and DNMT3A expression | progression and EMT formation of CRC | [56] | |
H19 | hypomethylation of the sixth CTCF-binding site in the differentially methylated region of IGF2/H19 | loss of imprinting of IGF2T → two forms of aberrant IGF2 expression | promotes microsatellite instability and oncogenesis | [62,63,64] |
MicroRNA & DNA methylation | ||||
miR-133b | promoter hypermethylation | HOXA9/ZEB1 pathway | inhibits migration and apoptosis; suppresses metastasis | [60,65] |
miR-149 | epigenetically silenced by DNA methylation | Specificity Protein 1 (SP1) | independent prognostic factor for overall survival | [66] |
miR-132 | downregulation by DNA hypermethylation | paxillin | associated with cell invasion | [59] |
miR-345 | CpG island promoter hypermethylation | BCL2-associated athanogene 3 (BAG3) | suppresses colon cancer cell proliferation and invasiveness | [67] |
miR-181a/135a/302c | DNA methylation-mediated repression | via repressing PLAG1/IGF2 signalling | promotes the microsatellite-unstable CRC development and 5-FU resistance | [58] |
miR-203 | directly targets DNMT3B | causes ABCG2 promoter methylation | predisposing CRC development by lowering expression of ABCG2. | [61] |
Non-Coding RNAs | Epigenetic Partner/Other Epigenetic Mediator | Target Gene | Tumorigenic Effects | Reference |
---|---|---|---|---|
Chromatin remodelling | ||||
DLEU1 | recruits SMARCA1, an essential subunit of the NURF chromatin remodelling complex | activation of KPNA3 | CRC development and progression | [40] |
CCAT1-L | regulates long-range chromatin interactions | activates the transcription of the MYC locus | both tumorigenesis and the metastatic process | [79] |
HOTAIR | reprograms chromatin organization in cooperation with the PRC2 complex | global epigenetic regulation | contributes to liver metastases in stage IV CRC patients | [79] |
Histone modification | ||||
MALAT1 | EZH2 | represses E-cadherin | promotes chemoresistance | [80] |
HULC | interacts with EZH2 | to repress NKD2 | oncogenic | [81] |
SNHG1 | interacts with PRC2 in the nucleus and acts as a miR-154-5p sponge in the cytoplasm | modulates histone methylation of KLF2 and CDKN2B | tumour progression | [74] |
CRNDE | binds to EZH2 | DUSP5/CDKN1A | positively correlates with advanced pathological stages and larger tumour sizes | [75] |
SNHG17 | binds to the EZH2 | p57 | promotes cell proliferation | [82] |
SH3PXD2A-AS1 | interacts with EZH2 | p57 and KLF2 | promotes cells proliferation, migration and invasion | [83] |
SNHG6 | recruits EZH2 to the p21 promoter | p21 | positively correlates with advanced tumour stage | [84] |
MEG3 | interacts with PRC2 and JARID2 to direct them to target promoters | Clusterin signalling pathway | inhibits cells proliferation and migration | [85] |
PINT | interacts with PRC2 to silence genes | p53 autoregulatory negative mechanism | inhibits proliferation of tumour cells | [86] |
PINT | interacts with PRC2 | EGR1 | inhibits tumour cell invasion | [87] |
PCAT6 | forms a complex with EZH2 | activates anti-apoptotic ARC | inhibits colon cancer cell apoptosis | [88] |
Histone modification/DNA methylation | ||||
Lnc34a | recruits DNMT3A via PHB2 and HDAC1 to methylate and deacetylate the MIR34A promoter simultaneously | epigenetically silence miR-34a | Increase colon cancer stem cells (CSCs) proliferation in late-stage CRC s. | [77] |
HOXA11-AS | scaffold for the chromatin modification factors PRC2, LSD1, and DNMT1 | lymph node metastasis | [89,90] |
Non-Coding RNAs | Mechanism of Action in AS | Target Gene | Tumorigenic Effect | Reference |
---|---|---|---|---|
LINC01133 | titrates SRSF6 away from its targets | inhibits EMT and metastasis | [141] | |
GAPLINC | binds to PSF and NONO | SNAI2 | promotes invasion in CRC | [144] |
MALAT1 | regulates SR splicing factor distribution in nuclear speckle domains | NA | [140] | |
MALAT1 | binds to SFPQ and releases oncogene PTBP2 from the SFPQ/PTBP2 complex | promotes tumour growth and metastasis in CRC | [143] | |
UXT-AS1 | isoform switching from UXT1 to UXT2 | UXT1 | promotes cell proliferation | [146] |
miR-1296 | represses SFPQ expression | SFPQ | accelerates CRC progression | [132] |
miR-92a | causing imbalanced expression of PTBP2 through AS-coupled nonsense mediated decay | RBM4 | contributes to progression and metabolic signature of CRC cells | [133] |
© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
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Amirkhah, R.; Naderi-Meshkin, H.; Shah, J.S.; Dunne, P.D.; Schmitz, U. The Intricate Interplay between Epigenetic Events, Alternative Splicing and Noncoding RNA Deregulation in Colorectal Cancer. Cells 2019, 8, 929. https://doi.org/10.3390/cells8080929
Amirkhah R, Naderi-Meshkin H, Shah JS, Dunne PD, Schmitz U. The Intricate Interplay between Epigenetic Events, Alternative Splicing and Noncoding RNA Deregulation in Colorectal Cancer. Cells. 2019; 8(8):929. https://doi.org/10.3390/cells8080929
Chicago/Turabian StyleAmirkhah, Raheleh, Hojjat Naderi-Meshkin, Jaynish S. Shah, Philip D. Dunne, and Ulf Schmitz. 2019. "The Intricate Interplay between Epigenetic Events, Alternative Splicing and Noncoding RNA Deregulation in Colorectal Cancer" Cells 8, no. 8: 929. https://doi.org/10.3390/cells8080929