Mechanism of long noncoding RNAs as transcriptional regulators in cancer

Figures & data

Table 1. Association with transcriptional factor (TF).

lncRNAs	Cancer type	Functions and phenotype	References
lncSOX4	Liver cancer	Recruits transcriptional factor STAT3 to the promoter of SOX4 gene for SOX4 activation, promotes hepatocellular carcinoma development	^[22]
HOXC-AS3	Gastric cancer	Induces transcriptional factor YBX1 to the target genes’ promoters that contain CCAAT-box, activatess cancer cell proliferation and migration.	^[23]
HOTAIR	Breast cancer	Serves as a scaffold to form a complex with HBXIP, c-myc and LSD1, activates transcription of c-myc target genes and drives carcinogenesis.	^[27]
PCAT19-long	Prostate cancer	Recruits HNRNPAB and other transcription factors to upregulate cell-cycle genes, promotes cell proliferation, migration and invasion.	^[30]
CCAT1	Squamous cell carcinomas (SCCs)	Acts as a scaffold, forms a complex with TP63 and SOX2, activates the expression of EGFR, MEK/ERK1/2 and PI3K/AKT cell signal. It promotes SCC cell proliferation both in vitro and in vivo	^[33]
SLNCR	Melanoma	Recruits AR to EGR1-bound genomic loci and switches EGR1-mediated transcriptional activation of p21Waf1/Cip1 to repressive status, promotes the development of melanoma	^[34]
PCAT1	Prostate cancer	Recruits AR and LSD1 to the enhancers of androgen late-response genes, promotes prostate cancer development.	^[35]
MALAT1	Breast cancer	Serves as a decoy to interact TEAD preventing TEAD from associating with its co-activator YAP and target gene promoters, suppresses cell metastasis.	^[37]
GAS5	Breast cancer	Acts as a decoy of GRE, prevents GR binding to GRE, controls cell apoptosis and inhibits breast cancer development.	^Citation[38,Citation39]
MALAT1	Liver cancer	Acts as a RNA decoy and releases DBC1 from SIRT1 to activate the enzymatic activity of SIRT1. It promotes deacetylation of p53 and cell proliferation and inhibits cell apoptosis.	^[40]

Figure 1. Association with transcriptional factors (TFs).

lncRNAs regulate gene transcription via influencing on TFs. (a) RNA guide: An lncRNA interacts with a single TF directly or indirectly and recruits the TF to the target gene promoters. (b) Molecular scaffold: An lncRNA is able to interact with multiple transcriptional regulators and promotes their recruitment to the target gene’s promoter. (c) RNA decoy: An lncRNA sequesters its associated TF from the target gene’s promoter or the latter’s complex.

Table 2. Modulating DNA methylation or histone modification enzyme.

lncRNAs	Cancer type	Functions and phenotype	References
lnc-β-Catm	Liver cancer	lnc-β-Catm serves as a co-activator of EZH2 to mediate the methylation of β-catenin and activates Wnt–β-catenin signalling in liver cancer stem cells (CSCs).	[47]
BCAR4	Breast cancer	Interacts with SNIP1 and releases the SNIP1’s inhibition of p300-dependent histone acetylation, it promotes H3K18 acetylation of the GLI2 target genes promoter. Besides, BCAR4 recruits PNUTS to interact with H3K18ac and disrupts inhibition of RNA Pol II, activating target genes of GLI2 expression, promoting tumour invasion and metastasis.	^[53]
SANT1	Renal cell carcinoma	Removes SFPQ/E2F1/HDAC1 suppressor complex from the promoter region and increases the acetylation of H3K27 to promote SLC47A2 expression	^[55]
TARID	Non-small cell lung cancer, head and neck squamous cell carcinoma, ovarian cancer	Induces an R-loop formation at the TCF21 promoter, recruits GADD45A and TET1. It leads to demethylation of TCF21 promoter, activates the tumour suppressor TCF21 and inhibit tumour development.	^[Citation68,Citation69]
EBIC	Cervical cancer	Recruits EZH2 to E-cadherin promoter, promotes cell metastasis and invasion	^[72]
AGAP2-AS1	Non-small cell lung cancer	recruits EZH2 and LSD1, represses tumour suppressors KLF2 and LATS2 transcription via H3K27me3, promotes cell proliferation and inhibits cell apoptosis.	^[80]
APC	Liver cancer	Recruits EZH2 to APC promoter, represses the expression of APC and activates Wnt/β-catenin signalling to promote the self-renewal of TIC cells.	^[81]
TUG1	Non-small cell lung cancer, liver cancer, glioma	Recruits EZH2 to target genes’ promoters, inhibits genes’ expression and cancer development. It also acts as a scaffold to recruit EZH2 and YY1 to repress differentiation genes in glioma stem cells (GSCs)	^[Citation82–Citation84]
LINC00152	Gastric cancer	Binds to EZH2 and represses p15 and p21 transcription to accelerate the cell cycle and promote cell proliferation.	^[85]
lncRNA-p21	Prostate cancer	Switches the activity of EZH2 from histone-methyltransferase to non-histone methyltransferase, induces EZH2 methylating STAT3 to promote neuroendocrine differentiation (NED).	^[86]
LNMAT1	Bladder cancer	Recruits hnRNPL to CCL2 promoter to enhance the expression of CCL2 by increasing H3K4me3. It induces CCL2 recruiting macrophages into the tumour and promotes lymphatic metastasis.	^[87]
EZR-AS1	Human oesophageal squamous cell carcinoma	Recruits histone methyltransferase SMYD3 to a binding site that is presented in a GC-rich region downstream of the EZR promoter. It causes the local enrichment of H3K4me3, promotes cell proliferation and invasion.	^[88]
LINC00473	Breast cancer	Recruits phosphorylated CREB or FUS to CCND1 promoter, maintaining the expression levels of CCND1. It can promote cell proliferation.	^[90]
BCAR4	Breast cancer	Recruits GLI2 to promoters of HK2 and PFBFK3, promotes H3K27 acetylation, cell migration and invasion.	^[91]
SATB2-AS1	Colorectal carcinoma	Recruits p300, acetylates H3K27 and H3K9 at the SATB2 promoter for SATB2 activation. It suppresses cell proliferation, migration and invasion.	^[56]

Figure 2. Modulating DNA methylation and histone modification enzymes.

lncRNAs mediate gene activation or repression through recruiting (1) or sequestering (2) epigenetic factors to influence the process of DNA methylation and/or histone modifications.

Table 3. Influencing on chromatin remodelling complex.

lncRNAs	Cancer type	Functions and phenotype	References
LncTCF7	Liver cancer	Recruits SWI/SNF complex to the promoter of TCF7, triggers Wnt signalling pathway to increase CSC self-renewal and cause cancer recurrence.	^[96]
SChLAP1	Pprostate cancer	Interacts with SWI/SNF complex, represses the expression of PTEN gene and promotes the process of tumorigenesis in prostate cancer cells.	^[97]
lncHand2-AS1	Liver cancer	Recruits INO80 chromatin remodelling complex to the promoter region of BMP signalling receptor BMPR1A, promotes the expression of BMPR1A, activates BMP signalling pathway, and maintains self-renewal of liver cancer stem cells.	^[104]

Figure 3. Influencing on chromatin remodelling complex.

(a) lncRNAs can recruit chromatin remodelling complexes such as SWI/SNF, ISW, INO80 to the target gene’s promoter, resulting in an alteration of chromatin structure that enables tightly condensed DNA to be accessed by transcription factors and gene activation. (b.) Conversely, other lncRNAs can sequester chromatin remodelling complexes from the targeting cis elements to trigger gene repression.

Table 4. Facilitating chromosomal looping.

lncRNAs	Cancer type	Functions and phenotype	References
IRAIN	acute myeloid leukaemia	Interacts with chromatin DNA, forming an intra-chromosomal enhancer/promoter loop to down-regulate the expression of IGF1R.	^[116]
Khps1	Osteosarcoma	Forms a RNA-DNA triplexes via a homopurine stretch upstream of the transcription start site of SPHK1, recruits p300/CBP and E2H1 to the SPHK1 promoter, and mediate the chromatin structure change of the target regions. It acts as an oncogenic molecule by up-regulating its deriving gene SPHK1’s expression.	^[118]
CCAT1-L	Colorectal cancer	Forms chromatin looping between the MYC enhancer and promoter, recruits CTCF to regulate MYC expression.	^[119]

Figure 4. Facilitating chromosomal looping.

lncRNAs helps to form enhancer:promoter looping to activate the transcription of the target genes.

Table 5. Interaction with RNA polymerase.

lncRNAs	Cancer type	Functions and phenotype	References
SLERT	Teratoma	Interacts with single DDX21 molecule to adjust the size of the DDX21 ring and relieve the inhibition of pol I, activates pol I -mediated transcription initiation directly and promote tumorgenesis.	^[122]
lncRNA AY	Hepatocellular carcinoma	Interacts with histone 1FX (H1FX) to the ITGAV promoter, enhances modification of H3K4Me3 and acH3K9/14 but reduces H3K27Me3 modification and H1FX occupation on ITGAV promoter. This causes a change of chromatin structure and pol II recruitment to target gene promoter for gene activation.	^[125]
NRCP	Ovarian cancer	Recruits both TF (STAT1) and RNA polymerase II as an intermediate to target gene’s promoter. The complex then increases the expression of downstream genes including glucose-6-phosphate isomerase to modulate cancer metabolism and promote ovarian cancer development.	^[128]

Figure 5. Associated with polymerases.

lncRNAs participate in gene transcription by influencing the function of polymerases through direct (a) or indirect (b) manner.

Table 6. Direct association with promoter.

lncRNAs	Cancer type	Functions and phenotype	References
ARHGAP5-AS1	Gastric cancer	ARHGAP5-AS1 interacts with ARHGAP5 promoter directly to promote the transcriptional expression of ARHGAP5. It promotes autophagy activity and allows cell survival in vitro and tumorigenesis in vivo.	^[129]
LEADeR (MIR205HG)	Prostate cancer	Directly binds to the Alu elements, leads to a transcriptional repression of the target gene possibly via buffering the activity of IRF1 on the promoter.	^[136]

Figure 6. Direct association with promoter.

An lncRNA binds to the target gene promoter directly and influences gene transcription likely through influencing the neighbouring transcriptional factor’s loading or activity.

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