and by MALAT1 RNA depletion using antisense oligonucleotides (ASOs), providing an early demonstration of lncRNA targeting as a potentially useful therapeutic
strategy in cancer treatment [37].
Subsequent studies ranging across several types of solid tumour such as
bladder cancer have corroborated the notion that MALAT1 overexpression mainly
contributes to tumour metastasis through the epigenetic dysregulation of gene
expression, rather than through its molecular activities of nuclear body formation
and pre-mRNA splicing regulation [38]. MALAT1 upregulation has also been
linked to epigenetic dysregulation in renal cell carcinoma (RCC), as well as reduced
overall survival among RCC patients [39]. In addition, the MALAT1-EZH2 interaction has been linked to metastasis-promoting E-Cadherin repression in osteosarcoma tumours associated with reduced survival [40]. Another lncRNA implicated
in driving cancer is Taurine Upregulated Gene 1 (TUG1) [41]. Overexpression of
TUG1 is generally associated with poor prognosis across several tumour types
including RCC [42] and bladder cancer [43]. In osteosarcoma, TUG1 has been
implicated as a positive regulator of EZH2 expression by directly binding and
inhibiting anti-EZH2 miRNA miR-144-3p, which enhances the metastatic potential
of osteosarcoma cells [44]. TUG1 is also upregulated in HCC, in which it promotes
cell proliferation and apoptosis resistance by directing PRC2, via EZH2, to epigenetically silence Krüppel-like factor 2 (KLF2) [45]. Thus, in many solid tumours,
TUG1 appears to act as an oncogenic lncRNA [46].
MIAT is rapidly emerging as a novel cancer-promoting long non-coding
RNA. The first indication of its relevance in cancer came when it was found to
be upregulated in aggressive forms of chronic lymphocytic leukaemia (CLL) [47].
In CLL, MIAT participates in a positive feedback loop with pluripotency-associated
transcription factor Oct4 that facilitates evasion of apoptosis in malignant B cells.
Recently, several studies have implicated MIAT in several different solid tumours,
among which MIAT has been found to be significantly upregulated in advancedstage NSCLC tumours. Upregulated MIAT has been shown both in vitro and
in vivo to be responsible for increased NSCLC tumour cell proliferation as well as
metastasis, in which it promotes the epigenetic activation of metastasis-associated
gene matrix metalloproteinase 9 (MMP9) [48].
3.2 Tumour-Suppressive lncRNAs: lincRNA-p21
and TP53BP1
LincRNA-p21 is a p53-directed lncRNA that is required to transcriptionally regulate
a substantial proportion of genes regulated by p53 and is itself a tumour suppressor,
as its knockdown significantly reduces apoptosis in cancer cells [49]. It is thought
that lincRNA-p21 may perform its tumour-suppressive function by guiding heterogeneous ribonucleoprotein particle K (hnRNP-K), both a coactivator and corepressor
of p53, to its target genes to coordinate its branch of the p53-directed DNA damage
response (DDR) gene regulatory network [49].
412
D. Hanly et al.
strategy in cancer treatment [37].
Subsequent studies ranging across several types of solid tumour such as
bladder cancer have corroborated the notion that MALAT1 overexpression mainly
contributes to tumour metastasis through the epigenetic dysregulation of gene
expression, rather than through its molecular activities of nuclear body formation
and pre-mRNA splicing regulation [38]. MALAT1 upregulation has also been
linked to epigenetic dysregulation in renal cell carcinoma (RCC), as well as reduced
overall survival among RCC patients [39]. In addition, the MALAT1-EZH2 interaction has been linked to metastasis-promoting E-Cadherin repression in osteosarcoma tumours associated with reduced survival [40]. Another lncRNA implicated
in driving cancer is Taurine Upregulated Gene 1 (TUG1) [41]. Overexpression of
TUG1 is generally associated with poor prognosis across several tumour types
including RCC [42] and bladder cancer [43]. In osteosarcoma, TUG1 has been
implicated as a positive regulator of EZH2 expression by directly binding and
inhibiting anti-EZH2 miRNA miR-144-3p, which enhances the metastatic potential
of osteosarcoma cells [44]. TUG1 is also upregulated in HCC, in which it promotes
cell proliferation and apoptosis resistance by directing PRC2, via EZH2, to epigenetically silence Krüppel-like factor 2 (KLF2) [45]. Thus, in many solid tumours,
TUG1 appears to act as an oncogenic lncRNA [46].
MIAT is rapidly emerging as a novel cancer-promoting long non-coding
RNA. The first indication of its relevance in cancer came when it was found to
be upregulated in aggressive forms of chronic lymphocytic leukaemia (CLL) [47].
In CLL, MIAT participates in a positive feedback loop with pluripotency-associated
transcription factor Oct4 that facilitates evasion of apoptosis in malignant B cells.
Recently, several studies have implicated MIAT in several different solid tumours,
among which MIAT has been found to be significantly upregulated in advancedstage NSCLC tumours. Upregulated MIAT has been shown both in vitro and
in vivo to be responsible for increased NSCLC tumour cell proliferation as well as
metastasis, in which it promotes the epigenetic activation of metastasis-associated
gene matrix metalloproteinase 9 (MMP9) [48].
3.2 Tumour-Suppressive lncRNAs: lincRNA-p21
and TP53BP1
LincRNA-p21 is a p53-directed lncRNA that is required to transcriptionally regulate
a substantial proportion of genes regulated by p53 and is itself a tumour suppressor,
as its knockdown significantly reduces apoptosis in cancer cells [49]. It is thought
that lincRNA-p21 may perform its tumour-suppressive function by guiding heterogeneous ribonucleoprotein particle K (hnRNP-K), both a coactivator and corepressor
of p53, to its target genes to coordinate its branch of the p53-directed DNA damage
response (DDR) gene regulatory network [49].
412
D. Hanly et al.