Another lncRNA of the p53 network, TP53TG1, undergoes CpG hypermethylation
and transcriptional repression of its genomic locus in CRC cell line HCT-116 and
acts as a tumour suppressor when overexpressed in p53-positive CRC cells [50].
TP53TG1 also directly interacts with YBX1, a dual DNA-/RNA-binding protein
that plays regulatory roles in gene transcription, pre-mRNA splicing and translation
[51]. TP53TG1 recovery in HCT116 cells reduces YBX1 occupancy of the PI3K
promoter, which in turn lowers PI3K expression and stabilises p53 levels. In addition,
TP53TG1 promoter hypermethylation and increased nuclear YBX1 are both associated with worse progression-free survival of CRC patients [50].
4 Strategies to Target lncRNAs Implicated in Cancer
Therapy Resistance
4.1 HOTAIR
Of all tumour types in which the therapeutic relevance of HOTAIR is being
investigated, some of the most remarkable insights have been made in ovarian
cancer (OC) studies. Two recent studies have done much to deepen our understanding of the influence of HOTAIR on OC response to chemotherapy [52, 53]. A
functional overlap had previously been established between PRC2 and NF-κB
in the response of breast cancer cells to genotoxic agents [54], and since HOTAIR
negatively regulates the expression of NF-κB pathway inhibitor Iκ-Bα [55], it
may in turn influence DDR via modulation of NF-κB activity in OC cells that
display HOTAIR upregulation, NF-κB hyperactivation and platinum drug resistance. HOTAIR overexpression in OC cells sensitive to cisplatin increased their
clonogenic potential, while the reverse was the case following HOTAIR knockdown in cisplatin-resistant cells. When HOTAIR-overexpressing cisplatin-sensitive
cells were injected into mice, the tumours formed showed enhanced growth and
cisplatin resistance [52]. Correspondingly, there were significant differences in
the expression levels of NF-κB pathway genes. Increased secretion of interleukin
6 (IL-6), along with several other cytokines, was also observed following HOTAIR
vector transfection [52]. Furthermore, treatment of non-transfected cells with
“HOTAIR-conditioned” media was sufficient to increase their resistance to cisplatin
in the presence of functional IL-6, implying that HOTAIR upregulation may
contribute to the previously reported role of IL-6 in shaping tumour microenvironments into “chemoresistant niches” [52, 56].
To therapeutically exploit the HOTAIR-NFκB axis in chemoresistant OC, a
strategy to target HOTAIR using peptide nucleic acids (PNAs) was developed
(Fig. 2a). In essence, PNAs are ASOs in which the sugar-phosphate backbone
is replaced with a synthetic peptide backbone, rendering them more stable than
conventional short interfering RNA (siRNA)s due to nuclease resistance and
increased thermal stability [57, 58]. A PNA was designed to target a minimum
Altered Long Non-coding RNA Expression in Cancer: Potential Biomarkers. . .
413
and transcriptional repression of its genomic locus in CRC cell line HCT-116 and
acts as a tumour suppressor when overexpressed in p53-positive CRC cells [50].
TP53TG1 also directly interacts with YBX1, a dual DNA-/RNA-binding protein
that plays regulatory roles in gene transcription, pre-mRNA splicing and translation
[51]. TP53TG1 recovery in HCT116 cells reduces YBX1 occupancy of the PI3K
promoter, which in turn lowers PI3K expression and stabilises p53 levels. In addition,
TP53TG1 promoter hypermethylation and increased nuclear YBX1 are both associated with worse progression-free survival of CRC patients [50].
4 Strategies to Target lncRNAs Implicated in Cancer
Therapy Resistance
4.1 HOTAIR
Of all tumour types in which the therapeutic relevance of HOTAIR is being
investigated, some of the most remarkable insights have been made in ovarian
cancer (OC) studies. Two recent studies have done much to deepen our understanding of the influence of HOTAIR on OC response to chemotherapy [52, 53]. A
functional overlap had previously been established between PRC2 and NF-κB
in the response of breast cancer cells to genotoxic agents [54], and since HOTAIR
negatively regulates the expression of NF-κB pathway inhibitor Iκ-Bα [55], it
may in turn influence DDR via modulation of NF-κB activity in OC cells that
display HOTAIR upregulation, NF-κB hyperactivation and platinum drug resistance. HOTAIR overexpression in OC cells sensitive to cisplatin increased their
clonogenic potential, while the reverse was the case following HOTAIR knockdown in cisplatin-resistant cells. When HOTAIR-overexpressing cisplatin-sensitive
cells were injected into mice, the tumours formed showed enhanced growth and
cisplatin resistance [52]. Correspondingly, there were significant differences in
the expression levels of NF-κB pathway genes. Increased secretion of interleukin
6 (IL-6), along with several other cytokines, was also observed following HOTAIR
vector transfection [52]. Furthermore, treatment of non-transfected cells with
“HOTAIR-conditioned” media was sufficient to increase their resistance to cisplatin
in the presence of functional IL-6, implying that HOTAIR upregulation may
contribute to the previously reported role of IL-6 in shaping tumour microenvironments into “chemoresistant niches” [52, 56].
To therapeutically exploit the HOTAIR-NFκB axis in chemoresistant OC, a
strategy to target HOTAIR using peptide nucleic acids (PNAs) was developed
(Fig. 2a). In essence, PNAs are ASOs in which the sugar-phosphate backbone
is replaced with a synthetic peptide backbone, rendering them more stable than
conventional short interfering RNA (siRNA)s due to nuclease resistance and
increased thermal stability [57, 58]. A PNA was designed to target a minimum
Altered Long Non-coding RNA Expression in Cancer: Potential Biomarkers. . .
413