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Page 14 of 23 Parsons et al. J Cancer Metastasis Treat 2018;4:19 I http://dx.doi.org/10.20517/2394-4722.2018.11

unclear as to how BORG modulates TRIM28 binding to specific chromatin regions that in turn modulates
a metastatic phenotype. One assumption is that specific sequence regions of BORG, outside the identified
TRIM28 binding sequence, interacts with TRIM28 or additional TRIM domain-containing TFs through
stacking interactions. These lncRNA structure-based interactions, mediate recruitment of the TRIM28
transcriptional protein complex to the proximal promoters of genes such as Cdkn1a and Gadd45a. BORG
also confers a unique transcriptional signature that is enriched for KRAS signaling, as compared to non-
metastatic D2.OR breast cancer cells. Further studies elucidating the role of BORG in human breast cancer
cells, as well as the regulatory role within the metastatic process, are warranted.

Prostate cancer associated transcript 1
Through genome wide RNA sequencing experiments, Prensner et al. identified prostate cancer associated
[183]
transcript 1 (PCAT1) as a lncRNA highly upregulated in metastatic prostate cancer samples, as well as those
considered high grade (i.e., stage II-IV). Upon knockdown of PCAT1 in prostate cancer cell lines, Prensner et al.
[183]
identified 370 genes expressed differentially, many of which were associated with cell-cycle progression and
mitosis, as well as cytoskeleton and microtubule regulation. Knockdown studies indicated that loss of PCAT1
resulted in an approximate 25% reduction in cellular proliferation, though the mechanism by which PCAT1
promotes an invasive phenotype is still unclear. One possibility may be due to the involvement of PCAT1
in the homologous recombination (HR) repair pathway. One can surmise, for instance, that as epithelial
progenitor cells proliferate, the acquisition of successive mutations within the genome across daughter
generations provides an opportunity for such cells to undergo a process such as EMT . Interestingly, PCAT1
[12]
is inversely correlated with BRCA2 expression in LNCaP cells, while the knockdown of PCAT1 resulted
in the upregulation of BRCA2, a crucial component of the DNA repair pathway [184,185] . Moreover, PCAT1
overexpression alters the formation of RAD51 and ɣ-H2aX foci after radiation-induced DNA damage,
while naturally occurring polymorphisms within the genome, such as rs7463708, can promote an enhanced
proliferative and migratory state within prostate cancer cell lines . Therefore, it is entirely plausible that the
[186]
reduction in chromosome stability via enhanced PCAT1 activity supports not only a pro-tumorigenic state,
but a pro-metastatic phenotype as well. Separating these two distinct yet equally important mechanisms will
be crucial in developing novel therapeutics to treat those with advanced prostate cancer.

CONCLUSION
Overall, lncRNAs play a multifaceted role in controlling the ncRNA network, which is vitally important
throughout embryogenesis and vertebrate development. Here we discussed the ways in which lncRNAs can
function as metastatic regulators, primarily by controlling epigenetic mechanisms, such as the recruitment
of co-repressor complexes including PRC1/2, as well as co-transcriptional complexes such as CREB/REST to
specific chromatin regions. Therefore, lncRNAs represent a unique class of ncRNA that operate as scaffolds
to bring specific chromosomal foci into proximity with epigenetic regulators and chromatin modifiers.
lncRNAs also control the appropriate expression of the DNA methylation machinery such as DNMT1,
and function as competitive binding partners for other ncRNAs with complementary sequences. As such,
lncRNAs serve as potent disruptors of conserved RNA-RNA regulatory networks.

Interestingly, lncRNA sequences are not highly conserved across species, however lncRNAs harbor a
conserved positional synteny that is linked with the regulatory function of that specific lncRNA. This presents
a unique challenge for the lncRNA field in that determining the importance of a lncRNA molecule found to
be differently expressed under certain experimental conditions cannot be further studied by assessing the
conservation of the sequence. Investigators will require a more nuanced approach in studying the landscape
of the surrounding genomic architecture, the proximity of certain DNA response elements, and if specific
protein coding genes flank the lncRNA, while also keeping in mind the state of the surrounding chromatin
architecture and determining if the DNA region is highly hetero- or eu-chromatinized [Figure 2C].